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30 results on '"Université Sciences et Technologies - Bordeaux 1 (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)"'

1. Practical identifiability analysis of a mechanistic model for the time to distant metastatic relapse and its application to renal cell carcinoma

Author

Arturo Álvarez-Arenas, Wilfried Souleyreau, Andrea Emanuelli, Lindsay S. Cooley, Jean-Christophe Bernhard, Andreas Bikfalvi, Sebastien Benzekry, Modélisation Mathématique pour l'Oncologie (MONC), Institut de Mathématiques de Bordeaux (IMB), Université Bordeaux Segalen - Bordeaux 2-Université Sciences et Technologies - Bordeaux 1 (UB)-Université de Bordeaux (UB)-Institut Polytechnique de Bordeaux (Bordeaux INP)-Centre National de la Recherche Scientifique (CNRS)-Université Bordeaux Segalen - Bordeaux 2-Université Sciences et Technologies - Bordeaux 1 (UB)-Université de Bordeaux (UB)-Institut Polytechnique de Bordeaux (Bordeaux INP)-Centre National de la Recherche Scientifique (CNRS)-Institut Bergonié [Bordeaux], UNICANCER-UNICANCER-Inria Bordeaux - Sud-Ouest, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria), Laboratoire Angiogenèse et Micro-environnement des Cancers (LAMC), Université Sciences et Technologies - Bordeaux 1 (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM), service d'urologie [CHU Bordeaux], CHU Bordeaux [Bordeaux], Méthodes computationnelles pour la prise en charge thérapeutique en oncologie : Optimisation des stratégies par modélisation mécaniste et statistique (COMPO), Inria Sophia Antipolis - Méditerranée (CRISAM), Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Centre de Recherche en Cancérologie de Marseille (CRCM), Aix Marseille Université (AMU)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), and Centre de Recherche en Cancérologie de Marseille (CRCM)

Subjects
[STAT.AP]Statistics [stat]/Applications [stat.AP], Ecology, [SDV.CAN]Life Sciences [q-bio]/Cancer, Survival Analysis, [INFO.INFO-MO]Computer Science [cs]/Modeling and Simulation, Kidney Neoplasms, Receptors, G-Protein-Coupled, Cellular and Molecular Neuroscience, Computational Theory and Mathematics, Modeling and Simulation, Genetics, [SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, Humans, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Neoplasm Recurrence, Local, Carcinoma, Renal Cell, Molecular Biology, Ecology, Evolution, Behavior and Systematics, [PHYS.PHYS.PHYS-DATA-AN]Physics [physics]/Physics [physics]/Data Analysis, Statistics and Probability [physics.data-an]
Abstract

Distant metastasis-free survival (DMFS) curves are widely used in oncology. They are classically analyzed using the Kaplan-Meier estimator or agnostic statistical models from survival analysis. Here we report on a method to extract more information from DMFS curves using a mathematical model of primary tumor growth and metastatic dissemination. The model depends on two parameters, α and μ, respectively quantifying tumor growth and dissemination. We assumed these to be lognormally distributed in a patient population. We propose a method for identification of the parameters of these distributions based on least-squares minimization between the data and the simulated survival curve. We studied the practical identifiability of these parameters and found that including the percentage of patients with metastasis at diagnosis was critical to ensure robust estimation. We also studied the impact and identifiability of covariates and their coefficients in α and μ, either categorical or continuous, including various functional forms for the latter (threshold, linear or a combination of both). We found that both the functional form and the coefficients could be determined from DMFS curves. We then applied our model to a clinical dataset of metastatic relapse from kidney cancer with individual data of 105 patients. We show that the model was able to describe the data and illustrate our method to disentangle the impact of three covariates on DMFS: a categorical one (Führman grade) and two continuous ones (gene expressions of the macrophage mannose receptor 1 (MMR) and the G Protein-Coupled Receptor Class C Group 5 Member A (GPRC5a) gene). We found that all had an influence in metastasis dissemination (μ), but not on growth (α).

Published
2022

2. Nouveaux mécanismes du développement des tumeurs cérébrales

Author

GUYON, Joris, Laboratoire Angiogenèse et Micro-environnement des Cancers (LAMC), Université Sciences et Technologies - Bordeaux 1 (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Bordeaux, Andreas Bikfalvi, STAR, ABES, Bikfalvi, Andreas, Javerzat, Sophie, Junier, Marie-Pierre, Chevet, Eric, and Carriere-Pazat, Audrey

Subjects
Glioblastome, Metabolism, Lactate dehydrogenases, Invasion, Angiogenèse, Lactate déshydrogénases, Angiogenesis, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Spheroids, Glioblastoma, Spheroïdes, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, Metabolisme
Abstract

Glioblastoma (GBM) is the most common and malignant primary brain tumor in adults. It can be recognized by its angiogenic and invasive growth, in addition to its altered metabolism.To study GBM, we developed three-dimensional models to better mimic its complex architecture of tumors. We have also refined in vitro methods, such as spheroid growth or invasion in collagen I matrix, to analyze certain characteristics of GBMs.Diffuse infiltration of GBMs complicates therapeutic management and is the cause of tumor recurrence. Invading cells into the healthy brain may form new tumor foci from the original tumor. A proteomic analysis of laser microdissection-captured human tumor pieces revealed potential actors of tumor invasion. PLP1 (proteolipid protein 1) and DNM1 (dynamin-1) was found enriched in the invasive part. In vitro inhibition of these protein lead to decrease GBM invasion and may represent potential therapeutic targets.By adapting their glycolytic or oxidative metabolism, GBM stem-like cells are able to resist chemo- and radiotherapy. Lactate is a central metabolite in brain physiology, involved in the astrocyte-neuron lactate shuttle, but also contributes to tumor development. We show herein that lactate fuels GBM anaplerosis by replenishing the TCA cycle in absence of glucose. Lactate dehydrogenases (LDH) catalyze the interconversion of pyruvate and lactate. Deletion of either LDHA or LDHB did not alter significantly GBM growth and invasion. However, ablation of both LDH isoforms led to a reduction of tumor growth, and, consequently, to an increase in mouse survival. Comparative transcriptomics and metabolomics revealed metabolic rewiring involving high oxidative phosphorylation (OxPhos) in the double LDHA/B KO group which sensitized tumors to cranial irradiation, massively improving mice survival. Survival was also increased when control mice were treated by an antiepileptic which targets LDH activity. Taken together, this highlights the complex metabolic network in which both LDH A and B are integrated and underscores that combined inhibition of LDHA and B is necessary to impact tumor development., Le glioblastome (GBM) est la tumeur cérébrale maligne la plus fréquente et la plus agressive chez l’adulte. Il est hautement prolifératif et invasif et se caractérise par une forte angiogenèse et la présence d’un métabolisme altéré.Afin de mieux comprendre son développement, nous avons créé des modèles cellulaires tridimensionnels permettant de se rapprocher au mieux de l’architecture complexe de la tumeur. Nous avons également affiné des méthodes in vitro, tels que des essais de croissance ou d’invasion en collagène de type I, pour analyser certaines caractéristiques des GBMs.L’infiltration diffus des GBMs complique la prise en charge thérapeutique et est à l’origine des récidives tumorales. Les cellules qui envahissent le parenchyme cérébral sain peuvent former de nouveaux foyers tumoraux à distance de la tumeur originelle. En utilisant une analyse de protéomique sur des échantillons de tumeurs humaines dans des cerveaux de souris récupérées par microdissection laser, nous avons identifié de potentiels acteurs de l’invasion tumorale. Les protéines PLP1 (proteolipid protein 1) et DNM1 (dynamin-1) ont été retrouvées enrichies dans la partie invasive. Leur inhibition in vitro a permis la réduction de la capacité invasive des GBMs et pourrait représenter de potentielles cibles thérapeutiques.En adaptant son métabolisme glycolytique et oxydatif, les cellules de GBM sont capables de résister à la chimio- et radiothérapie. Le lactate est un des métabolites centraux de la physiologie cérébrale, il est impliqué dans la navette astrocyte-neurone ainsi que dans le développement tumoral. En l’absence de glucose, le lactate alimente la production d’énergie des GBMs par le biais du cycle de Krebs. Les lactates déshydrogénases (LDHs) sont les enzymes qui catalysent l’interconversion du pyruvate et du lactate. La simple perte d’expression des isoformes LDHA ou LDHB ne perturbe pas significativement le développement des GBMs. Cependant, la double extinction de LDHA et LDHB (KO LDHA/B) induit une réduction de la croissance tumorale, de l’invasion et en conséquence, allonge la survie des souris. Les analyses comparatives des données de transcriptomique et de métabolomique révèlent que la lignée double KO LDHA/B augmente le métabolisme oxydatif sensibilisant la tumeur à l’irradiation et augmentant la survie des souris. L’utilisation d’un médicament antiépileptique inhibiteur de l’activité de LDHA et LDHB a permis d’augmenter la survie des souris en association avec le bevacizumab, un médicament anticancéreux ciblant l’angiogenèse. Cette étude met en évidence le réseau métabolique complexe dans lequel LDHA et LDHB sont intriqués. Elle souligne l’importance de la double inhibition de LDHA/LDHB pour impacter le développement tumoral.

Published
2021

3. Experimental and computational modeling for signature and biomarker discovery of renal cell carcinoma progression

Author

Cooley, Lindsay, Rudewicz, Justine, Souleyreau, Wilfried, Emanuelli, Andrea, Alvarez-Arenas, Arturo, Clarke, Kim, Falciani, Francesco, Dufies, Maeva, Lambrechts, Diether, Modave, Elodie, Chalopin-Fillot, Domitille, Pineau, Raphael, Ambrosetti, Damien, Bernhard, Jean-Christophe, Ravaud, Alain, Négrier, Sylvie, Ferrero, Jean-Marc, Pagès, Gilles, Benzekry, Sebastien, Nikolski, Macha, Bikfalvi, Andreas, Institut de biochimie et génétique cellulaires (IBGC), Université Bordeaux Segalen - Bordeaux 2-Centre National de la Recherche Scientifique (CNRS), Immunology from Concept and Experiments to Translation (ImmunoConcept), Centre National de la Recherche Scientifique (CNRS)-Université de Bordeaux (UB), Méthodes computationnelles pour la prise en charge thérapeutique en oncologie : Optimisation des stratégies par modélisation mécaniste et statistique (COMPO), Inria Sophia Antipolis - Méditerranée (CRISAM), Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Centre de Recherche en Cancérologie de Marseille (CRCM), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Aix Marseille Université (AMU), Centre de Bioinformatique de Bordeaux (CBIB), CGFB, Laboratoire Angiogenèse et Micro-environnement des Cancers (LAMC), Université Sciences et Technologies - Bordeaux 1 (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM), Modélisation Mathématique pour l'Oncologie (MONC), Institut de Mathématiques de Bordeaux (IMB), Université Bordeaux Segalen - Bordeaux 2-Université Sciences et Technologies - Bordeaux 1 (UB)-Université de Bordeaux (UB)-Institut Polytechnique de Bordeaux (Bordeaux INP)-Centre National de la Recherche Scientifique (CNRS)-Université Bordeaux Segalen - Bordeaux 2-Université Sciences et Technologies - Bordeaux 1 (UB)-Université de Bordeaux (UB)-Institut Polytechnique de Bordeaux (Bordeaux INP)-Centre National de la Recherche Scientifique (CNRS)-Institut Bergonié [Bordeaux], UNICANCER-UNICANCER-Inria Bordeaux - Sud-Ouest, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria), Mathematical Oncology Laboratory [Ciudad Real] (MôLAB), Universidad de Castilla-La Mancha = University of Castilla-La Mancha (UCLM), University of Liverpool, Centre Scientifique de Monaco (CSM), Institut de Recherche sur le Cancer et le Vieillissement (IRCAN), Université Nice Sophia Antipolis (1965 - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), Leuven Center for Cancer Biology (VIB-KU-CCB), Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven)-Vlaams Instituut voor Biotechnologie [Ghent, Belgique] (VIB), Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS), Université de Bordeaux (UB), Hôpital Pasteur [Nice] (CHU), service d'urologie [CHU Bordeaux], CHU Bordeaux [Bordeaux], Centre Léon Bérard [Lyon], Centre de Lutte contre le Cancer Antoine Lacassagne [Nice] (UNICANCER/CAL), UNICANCER-Université Côte d'Azur (UCA), Aix Marseille Université (AMU)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU)-Institut Paoli-Calmettes, and Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)

Subjects
EXPRESSION, Biochemistry & Molecular Biology, PROGNOSIS, Tumor model, INHIBITION, Prognostic markers renal cell carcinoma, SUNITINIB, Models, Biological, VALIDATION, Metastasis, SAA2, Mice, Cell Line, Tumor, Biomarkers, Tumor, Animals, Humans, R PACKAGE, Carcinoma, Renal Cell, RC254-282, Science & Technology, Gene Expression Profiling, Research, Computational model, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, Computational Biology, Disease Management, SERUM AMYLOID ALPHA, Genomics, Prognosis, CANCER, Systems biology approach, Kidney Neoplasms, Disease Models, Animal, Gene Ontology, CFB, Oncology, SURVIVAL, Heterografts, Disease Susceptibility, [INFO.INFO-BI]Computer Science [cs]/Bioinformatics [q-bio.QM], Life Sciences & Biomedicine
Abstract

Background Renal Cell Carcinoma (RCC) is difficult to treat with 5-year survival rate of 10% in metastatic patients. Main reasons of therapy failure are lack of validated biomarkers and scarce knowledge of the biological processes occurring during RCC progression. Thus, the investigation of mechanisms regulating RCC progression is fundamental to improve RCC therapy. Methods In order to identify molecular markers and gene processes involved in the steps of RCC progression, we generated several cell lines of higher aggressiveness by serially passaging mouse renal cancer RENCA cells in mice and, concomitantly, performed functional genomics analysis of the cells. Multiple cell lines depicting the major steps of tumor progression (including primary tumor growth, survival in the blood circulation and metastatic spread) were generated and analyzed by large-scale transcriptome, genome and methylome analyses. Furthermore, we performed clinical correlations of our datasets. Finally we conducted a computational analysis for predicting the time to relapse based on our molecular data. Results Through in vivo passaging, RENCA cells showed increased aggressiveness by reducing mice survival, enhancing primary tumor growth and lung metastases formation. In addition, transcriptome and methylome analyses showed distinct clustering of the cell lines without genomic variation. Distinct signatures of tumor aggressiveness were revealed and validated in different patient cohorts. In particular, we identified SAA2 and CFB as soluble prognostic and predictive biomarkers of the therapeutic response. Machine learning and mathematical modeling confirmed the importance of CFB and SAA2 together, which had the highest impact on distant metastasis-free survival. From these data sets, a computational model predicting tumor progression and relapse was developed and validated. These results are of great translational significance. Conclusion A combination of experimental and mathematical modeling was able to generate meaningful data for the prediction of the clinical evolution of RCC. Supplementary Information The online version contains supplementary material available at 10.1186/s12943-021-01416-5.

Published
2021

4. Variations on the theme of podosomes: A matter of context

Author

IJsbrand M. Kramer, Elisabeth Génot, Florian Alonso, Pirjo Spuul, Thomas Daubon, Centre de recherche Cardio-Thoracique de Bordeaux [Bordeaux] (CRCTB), Université Bordeaux Segalen - Bordeaux 2-CHU Bordeaux [Bordeaux]-Institut National de la Santé et de la Recherche Médicale (INSERM), Tallinn University of Technology (TTÜ), Laboratoire Angiogenèse et Micro-environnement des Cancers (LAMC), Université Sciences et Technologies - Bordeaux 1-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Sciences et Technologies - Bordeaux 1 (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM), and CCSD, Accord Elsevier

Subjects
0301 basic medicine, Basement membrane, Microenvironment, Podosome, Angiogenesis, [SDV]Life Sciences [q-bio], Cell, Antigen presentation, Gene Expression, Neovascularization, Physiologic, Context (language use), Biology, Extracellular matrix, 03 medical and health sciences, 0302 clinical medicine, Invasion, Mechanosensing, Cell Movement, medicine, Macrophage, Molecular Biology, Antigen Presentation, Macrophages, Cell Membrane, Dendritic Cells, Cell Biology, [SDV] Life Sciences [q-bio], Endothelial stem cell, 030104 developmental biology, medicine.anatomical_structure, 030220 oncology & carcinogenesis, Podosomes, Endothelium, Vascular, Neuroscience, Signal Transduction
Abstract

International audience; Extensive in vitro studies have described podosomes as actin-based structures at the plasma membrane, connecting the cell with its extracellular matrix and endowed with multiple capabilities. Contractile actin-myosin cables assemble them into a network that constitutes a multifaceted cellular superstructure taking different forms - with common characteristics - but manifesting different properties depending on the context of study. Their morphology and their role in cell functioning and behavior are therefore now apprehended in in vivo or in vitro situations relevant to physiological processes. We focus here on three of them, namely: macrophage migration, antigen presentation by dendritic cells and endothelial cell sprouting during angiogenesis to highlight the characteristics of podosomes and their functioning shaped by the microenvironment.

Published
2019

5. In Silico Investigation of the New UK (B.1.1.7) and South African (501Y.V2) SARS-CoV-2 Variants with a Focus at the ACE2–Spike RBD Interface

Author

Abdel-Majid Khatib, Bruno O. Villoutreix, Anne-Geneviève Marcelin, Vincent Calvez, Maladies neurodéveloppementales et neurovasculaires (NeuroDiderot (UMR_S_1141 / U1141)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Institut Pierre Louis d'Epidémiologie et de Santé Publique (iPLESP), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire Angiogenèse et Micro-environnement des Cancers (LAMC), Université Sciences et Technologies - Bordeaux 1-Institut National de la Santé et de la Recherche Médicale (INSERM), Gestionnaire, HAL Sorbonne Université 5, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), and Université Sciences et Technologies - Bordeaux 1 (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
2019-20 coronavirus outbreak, Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), In silico, UK and South African variants, ACE2, Biology, Antibodies, Viral, in silico stability prediction, Article, lcsh:Chemistry, 03 medical and health sciences, South Africa, 0302 clinical medicine, Humans, Computer Simulation, Protein Interaction Domains and Motifs, lcsh:QH301-705.5, 030304 developmental biology, chemistry.chemical_classification, Genetics, 0303 health sciences, Binding Sites, Strain (chemistry), SARS-CoV-2, Spike Protein, COVID-19, spike, Pathogenicity, Antibodies, Neutralizing, United Kingdom, Amino acid, lcsh:Biology (General), lcsh:QD1-999, chemistry, Amino Acid Substitution, [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie, Spike Glycoprotein, Coronavirus, Receptors, Virus, Spike (software development), [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Angiotensin-Converting Enzyme 2, 030217 neurology & neurosurgery, Protein Binding
Abstract

SARS-CoV-2 exploits angiotensin-converting enzyme 2 (ACE2) as a receptor to invade cells. It has been reported that the UK and South African strains may have higher transmission capabilities, eventually due to amino acid substitutions on the SARS-CoV-2 Spike protein. The pathogenicity seems modified but is still under investigation. Here we used the experimental structure of the Spike RBD domain co-crystallized with part of the ACE2 receptor and several in silico methods to analyze the possible impacts of three amino acid replacements (Spike K417N, E484K, N501Y) with regard to ACE2 binding. We found that the N501Y replacement in this region of the interface (present in both UK and South African strains) should be favorable for the interaction with ACE2 while the K417N and E484K substitutions (South African) would seem unfavorable. It is unclear if the N501Y substitution in the South African strain could counterbalance the predicted less favorable (regarding binding) K417N and E484K Spike replacements. Our finding suggests that, if indeed the South African strain has a high transmission level, this could be due to the N501Y replacement and/or to substitutions in regions outside the direct Spike-ACE2 interface.HihglightsTransmission of the UK and possibly South African SARS-CoV-2 strains appears substantially increased compared to other variantsThis could be due, in part, to increased affinity between the variant Spike proteins and ACE2We investigated in silico the 3D structure of the Spike-ACE2 complex with a focus on Spike K417N, E484K and N501YThe N501Y substitution is predicted to increase the affinity toward ACE2 (UK strain) with subsequent enhanced transmissibility and possibly pathogenicityAdditional substitutions at positions 417 and 484 (South African strain) may pertub the interaction with ACE2 raising questions about transmissibility and pathogenicity

Published
2021

6. Different cardiovascular and pulmonary phenotypes for single- and double-knock-out mice deficient in BMP9 and BMP10

Author

Nihel Berrebeh, Emmanuelle Tillet, Hequn Liu, Christophe Guignabert, Ly Tu, Sabine Bailly, Christophe Battail, Martina Rossi, Nicolas Chaumontel, Marie Ouarné, Laurent Savale, Thomas Daubon, Marc Humbert, Agnès Desroches-Castan, Christine Mallet, Caroline Roelants, Elise Helfer, Claire Bouvard, Pascale Perret, Andreas Bikfalvi, Bailly, Sabine, Famille BMP dans l'angiogenèse et la lymphangiogenèse (BAL), BioSanté (UMR BioSanté), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes (UGA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes (UGA), Université Paris-Saclay, Invasion mechanisms in angiogenesis and cancer (IMAC), CEA- Saclay (CEA), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Adhésion et Inflammation (LAI), Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre Chirurgical Marie Lannelongue (CCML), Inovarion, Laboratoire Angiogenèse et Micro-environnement des Cancers (LAMC), Université Sciences et Technologies - Bordeaux 1 (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM), AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre), Institut de biochimie et génétique cellulaires (IBGC), Université Bordeaux Segalen - Bordeaux 2-Centre National de la Recherche Scientifique (CNRS), Radiopharmaceutiques biocliniques (LRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes (UGA), ANR-17-CE14-0006,B9inPAH,BMP9 un modulateur clef du tonus vasculaire dans l'hypertension artérielle pulmonaire : une nouvelle cible thérapeutique à haut potentiel(2017), ANR-15-IDEX-0002,UGA,IDEX UGA(2015), ANR-17-EURE-0003,CBH-EUR-GS,CBH-EUR-GS(2017), ANR-11-INBS-0006,FLI,France Life Imaging(2011), European Project: EQU202003010188,V.A.Cure-814316, DAUBON, Thomas, BMP9 un modulateur clef du tonus vasculaire dans l'hypertension artérielle pulmonaire : une nouvelle cible thérapeutique à haut potentiel - - B9inPAH2017 - ANR-17-CE14-0006 - AAPG2017 - VALID, IDEX UGA - - UGA2015 - ANR-15-IDEX-0002 - IDEX - VALID, CBH-EUR-GS - - CBH-EUR-GS2017 - ANR-17-EURE-0003 - EURE - VALID, Infrastructures - France Life Imaging - - FLI2011 - ANR-11-INBS-0006 - INBS - VALID, H2020 MarieSkłodowska-Curie Actions - V.A.Cure-814316 - EQU202003010188 - INCOMING, Famille BMP dans l'angiogenèse et la lymphangiogenèse (BAL ), Biologie du Cancer et de l'Infection (BCI ), Assistance Publique - Hôpitaux de Marseille (APHM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Centre chirurgical Marie Lannelongue, and Université Sciences et Technologies - Bordeaux 1-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
0301 basic medicine, medicine.medical_specialty, Physiology, Activin Receptors, Type II, [SDV]Life Sciences [q-bio], 030204 cardiovascular system & hematology, Pathogenesis, Mice, 03 medical and health sciences, 0302 clinical medicine, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Physiology (medical), Internal medicine, pulmonary hypertension, Growth Differentiation Factor 2, medicine, bone morphogenetic proteins, Animals, Hypoxia, Lung, Mice, Knockout, Endothelin receptor antagonist, business.industry, medicine.disease, Pulmonary hypertension, Bosentan, 3. Good health, [SDV.MHEP.CSC] Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, [SDV] Life Sciences [q-bio], vascular anomalies, Phenotype, 030104 developmental biology, Endocrinology, medicine.anatomical_structure, high-output heart failure, Heart failure, Knockout mouse, Vascular resistance, medicine.symptom, Cardiology and Cardiovascular Medicine, business, Vasoconstriction, pulmonary vascular remodeling, medicine.drug
Abstract

Aims BMP9 and BMP10 mutations were recently identified in patients with pulmonary arterial hypertension, but their specific roles in the pathogenesis of the disease are still unclear. We aimed to study the roles of BMP9 and BMP10 in cardiovascular homeostasis and pulmonary hypertension using transgenic mouse models deficient in Bmp9 and/or Bmp10. Methods and results Single- and double-knockout mice for Bmp9 (constitutive) and/or Bmp10 (tamoxifen inducible) were generated. Single-knock-out (KO) mice developed no obvious age-dependent phenotype when compared with their wild-type littermates. However, combined deficiency in Bmp9 and Bmp10 led to vascular defects resulting in a decrease in peripheral vascular resistance and blood pressure and the progressive development of high-output heart failure and pulmonary hemosiderosis. RNAseq analysis of the lungs of the double-KO mice revealed differential expression of genes involved in inflammation and vascular homeostasis. We next challenged these mice to chronic hypoxia. After 3 weeks of hypoxic exposure, Bmp10-cKO mice showed an enlarged heart. However, although genetic deletion of Bmp9 in the single- and double-KO mice attenuated the muscularization of pulmonary arterioles induced by chronic hypoxia, we observed no differences in Bmp10-cKO mice. Consistent with these results, endothelin-1 levels were significantly reduced in Bmp9 deficient mice but not Bmp10-cKO mice. Furthermore, the effects of BMP9 on vasoconstriction were inhibited by bosentan, an endothelin receptor antagonist, in a chick chorioallantoic membrane assay. Conclusions Our data show redundant roles for BMP9 and BMP10 in cardiovascular homeostasis under normoxic conditions (only combined deletion of both Bmp9 and Bmp10 was associated with severe defects) but highlight specific roles under chronic hypoxic conditions. We obtained evidence that BMP9 contributes to chronic hypoxia-induced pulmonary vascular remodelling, whereas BMP10 plays a role in hypoxia-induced cardiac remodelling in mice.

Published
2021

7. PRL-2 phosphatase is required for vascular morphogenesis and angiogenic signaling

Author

Poulet, Mathilde, Sirois, Jacinthe, Boyé, Kevin, Uetani, Noriko, Hardy, Serge, Daubon, Thomas, Dubrac, Alexandre, Tremblay, Michel, Bikfalvi, Andreas, Laboratoire Angiogenèse et Micro-environnement des Cancers (LAMC), Université Sciences et Technologies - Bordeaux 1-Institut National de la Santé et de la Recherche Médicale (INSERM), McGill University = Université McGill [Montréal, Canada], Centre de recherche du CHU Sainte-Justine [Montreal], CHU Sainte Justine [Montréal]-Université de Montréal (UdeM), Université de Montréal (UdeM), Université Sciences et Technologies - Bordeaux 1 (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de recherche du CHU Sainte-Justine / Research Center of the Sainte-Justine University Hospital [Montreal, Canada], Université de Montréal (UdeM)-CHU Sainte Justine [Montréal], and DAUBON, Thomas

Subjects
Male, endocrine system, endocrine system diseases, Vascular Malformations, [SDV]Life Sciences [q-bio], Neovascularization, Physiologic, Retina, Article, Immediate-Early Proteins, Mice, Cell Movement, Human Umbilical Vein Endothelial Cells, Animals, Humans, lcsh:QH301-705.5, Cells, Cultured, Mice, Knockout, Endothelial Cells, Cardiovascular biology, [SDV] Life Sciences [q-bio], Mice, Inbred C57BL, lcsh:Biology (General), cardiovascular system, Female, sense organs, Angiogenesis, Protein Tyrosine Phosphatases, hormones, hormone substitutes, and hormone antagonists, Signal Transduction
Abstract

Protein tyrosine phosphatases are essential modulators of angiogenesis and have been identified as novel therapeutic targets in cancer and anti-angiogenesis. The roles of atypical Phosphatase of Regenerative Liver (PRL) phosphatases in this context remain poorly understood. Here, we investigate the biological function of PRL phosphatases in developmental angiogenesis in the postnatal mouse retina and in cell culture. We show that endothelial cells in the retina express PRL-2 encoded by the Ptp4a2 gene, and that inducible endothelial and global Ptp4a2 mutant mice exhibit defective retinal vascular outgrowth, arteriovenous differentiation, and sprouting angiogenesis. Mechanistically, PTP4A2 deletion limits angiogenesis by inhibiting endothelial cell migration and the VEGF-A, DLL-4/NOTCH-1 signaling pathway. This study reveals the importance of PRL-2 as a modulator of vascular development., Poulet et al investigate the role for the PRL-2 phosphatase in mouse retina, and find that loss of PRL-2 impairs vascular outgrowth and arteriovenous patterning. They find that PRL-2 s regulates endothelial cell migration and sprouting angiogenesis and acts through VEGF and NOTCH1 signalling.

Published
2020

8. Plk1, upregulated by HIF-2, mediates metastasis and drug resistance of clear cell renal cell carcinoma

Author

Emmanuel Chamorey, Wilfried Souleyreau, Alain Ravaud, Xingkang He, Papa Diogop Ndiaye, Lindsay S. Cooley, Sandy Giuliano, Nathalie M. Mazure, Benoit Beuselinck, Jessica Zucman-Rossi, Damien Ambrosetti, Patrick Auberger, Anais Hagege, Nathalie Rioux-Leclercq, Renaud Schiappa, Julien Parola, Karim Bensalah, Delphine Borchiellini, Stéphanie Torrino, Gilles Pagès, Andreas Bikfalvi, Yihai Cao, Nicolas Nottet, Baharia Mograbi, Jean-Christophe Bernhard, Annelies Verbiest, Maeva Dufies, mazure, nathalie, Centre Scientifique de Monaco (CSM), Laboratoire International Associé Réponse des Organismes et Populations face au Stress Environnemental - Université Côte d’Azur - Centre Scientifique de Monaco (LIA ROPSE), Université Côte d’Azur - Centre Scientifique de Monaco, University Hospitals Leuven [Leuven], Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven), Laboratoire Angiogenèse et Micro-environnement des Cancers (LAMC), Université Sciences et Technologies - Bordeaux 1 (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de Recherche sur le Cancer et le Vieillissement (IRCAN), Université Nice Sophia Antipolis (1965 - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), Centre de Lutte contre le Cancer Antoine Lacassagne [Nice] (UNICANCER/CAL), UNICANCER-Université Côte d'Azur (UCA), Karolinska Institutet [Stockholm], Centre méditerranéen de médecine moléculaire (C3M), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Côte d'Azur (UCA), Institut de pharmacologie moléculaire et cellulaire (IPMC), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Paris Cité (UPCité), CHU Pontchaillou [Rennes], CHU Bordeaux [Bordeaux], Hôpital Pasteur [Nice] (CHU), Centre Hospitalier Universitaire de Nice (CHU Nice), Université Sciences et Technologies - Bordeaux 1-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Nice Sophia Antipolis (... - 2019) (UNS), Centre National de la Recherche Scientifique (CNRS)-Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Université Côte d'Azur (UCA), and Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université de Paris (UP)

Subjects
0301 basic medicine, Life Sciences & Biomedicine - Other Topics, Embryo, Nonmammalian, [SDV]Life Sciences [q-bio], Medicine (miscellaneous), Cell Cycle Proteins, Drug resistance, Metastasis, Cohort Studies, Tumour biomarkers, Mice, 0302 clinical medicine, Antineoplastic Combined Chemotherapy Protocols, Biology (General), Neoplasm Metastasis, Zebrafish, Sunitinib, Kinase, Kidney Neoplasms, 3. Good health, Up-Regulation, [SDV] Life Sciences [q-bio], Multidisciplinary Sciences, Gene Expression Regulation, Neoplastic, Cancer therapeutic resistance, 030220 oncology & carcinogenesis, Science & Technology - Other Topics, Female, General Agricultural and Biological Sciences, Life Sciences & Biomedicine, medicine.drug, QH301-705.5, Mice, Nude, Protein Serine-Threonine Kinases, PLK1, General Biochemistry, Genetics and Molecular Biology, Article, 03 medical and health sciences, Targeted therapies, Downregulation and upregulation, In vivo, Cell Line, Tumor, Proto-Oncogene Proteins, medicine, Animals, Humans, Biology, Carcinoma, Renal Cell, Cell Proliferation, Science & Technology, business.industry, medicine.disease, Clear cell renal cell carcinoma, 030104 developmental biology, Drug Resistance, Neoplasm, Cancer research, business, Tumour angiogenesis
Abstract

Polo-like kinase 1 (Plk1) expression is inversely correlated with survival advantages in many cancers. However, molecular mechanisms that underlie Plk1 expression are poorly understood. Here, we uncover a hypoxia-regulated mechanism of Plk1-mediated cancer metastasis and drug resistance. We demonstrated that a HIF-2-dependent regulatory pathway drives Plk1 expression in clear cell renal cell carcinoma (ccRCC). Mechanistically, HIF-2 transcriptionally targets the hypoxia response element of the Plk1 promoter. In ccRCC patients, high expression of Plk1 was correlated to poor disease-free survival and overall survival. Loss-of-function of Plk1 in vivo markedly attenuated ccRCC growth and metastasis. High Plk1 expression conferred a resistant phenotype of ccRCC to targeted therapeutics such as sunitinib, in vitro, in vivo, and in metastatic ccRCC patients. Importantly, high Plk1 expression was defined in a subpopulation of ccRCC patients that are refractory to current therapies. Hence, we propose a therapeutic paradigm for improving outcomes of ccRCC patients., Dufies et al. find high Plk1 expression levels in aggressive clear cell renal cell carcinoma and discover that Plk1 is transcriptionally upregulated in a manner dependent on HIF-2. They also find that high Plk1 expression is correlated to a poor prognosis and resistance to tyrosine kinase inhibitor against VEGF receptor, suggesting a critical role for hypoxia/HIF-2-induced Plk1 in disease progression.

Published
2020

9. Proprotein convertases: Key players in inflammation-related malignancies and metastasis

Author

Geraldine Siegfried, Abdel-Majid Khatib, Serge Evrard, Jean Descarpentrie, Laboratoire Angiogenèse et Micro-environnement des Cancers (LAMC), Université Sciences et Technologies - Bordeaux 1-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Sciences et Technologies - Bordeaux 1 (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Bergonié [Bordeaux], UNICANCER, and CCSD, Accord Elsevier

Subjects
0301 basic medicine, Cancer Research, Chemokine, Carcinogenesis, [SDV]Life Sciences [q-bio], Inflammation, Article, Metastasis, 03 medical and health sciences, 0302 clinical medicine, Neoplasms, medicine, Tumor Microenvironment, Animals, Humans, Enzyme Inhibitors, Neoplasm Metastasis, Antineoplastic Agents, Alkylating, Tumor microenvironment, biology, Substrates, business.industry, Protein maturation, medicine.disease, Extravasation, 3. Good health, [SDV] Life Sciences [q-bio], Disease Models, Animal, 030104 developmental biology, Oncology, α1-PDX, Tumor progression, 030220 oncology & carcinogenesis, Cancer cell, biology.protein, Cancer research, Disease Progression, Selectins, Proprotein Convertases, medicine.symptom, Chemokines, business, Signal Transduction
Abstract

Many cancers occur from locations of inflammation due to chronic irritation and/or infection. Tumor microenvironment contains various different inflammatory cells and mediators that orchestrate diverse neoplastic processes, including proliferation, survival, adhesion and migration. In parallel, tumor cells have adapted some of the signaling molecules used by inflammatory cells, such as selectins and chemokines as well as their receptors for invasion, extravasation and subsequently metastasis. Expression and/or activation of the majority of these molecules is mediated by the proprotein convertases (PCs); proteases expressed by both tumor cells and inflammatory cells. This review analyzes the potential role of these enzymatic system in inflammation-associated cancer impacting on the malignant and metastatic potential of cancer cells, describing the possible use of PCs as a new anti-inflammatory therapeutic approach to tumor progression and metastasis., Highlights • Proteins maturation by the proprotein convertases plays important role in inflammation-related cancer and metastasis. • Protein precursors require the proprotein convertases for the induction of inflammation. • Understanding of the molecular mechanism linking the proprotein convertases to inflammation will allow novel therapies. • Inhibitors of the proprotein convertases constitute great potential for cancer treatment.

Published
2020

10. A 3D Spheroid Model for Glioblastoma

Author

Gaëlle Recher, Andreas Bikfalvi, Thomas Daubon, Nadège Pujol, Laetitia Andrique, Joris Guyon, Gro V. Røsland, Laboratoire Angiogenèse et Micro-environnement des Cancers (LAMC), Université Sciences et Technologies - Bordeaux 1-Institut National de la Santé et de la Recherche Médicale (INSERM), University of Bergen (UiB), Institut de biochimie et génétique cellulaires (IBGC), Université Bordeaux Segalen - Bordeaux 2-Centre National de la Recherche Scientifique (CNRS), Laboratoire Photonique, Numérique et Nanosciences (LP2N), Université de Bordeaux (UB)-Institut d'Optique Graduate School (IOGS)-Centre National de la Recherche Scientifique (CNRS), Université Sciences et Technologies - Bordeaux 1 (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Recher, Gaelle

Subjects
0301 basic medicine, Cellular pathology, General Chemical Engineering, [PHYS.PHYS.PHYS-BIO-PH]Physics [physics]/Physics [physics]/Biological Physics [physics.bio-ph], Cell Culture Techniques, Biology, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, Imaging, Three-Dimensional, 0302 clinical medicine, In vivo, Spheroids, Cellular, medicine, Humans, Tumor growth, ComputingMilieux_MISCELLANEOUS, [PHYS.PHYS.PHYS-BIO-PH] Physics [physics]/Physics [physics]/Biological Physics [physics.bio-ph], General Immunology and Microbiology, Brain Neoplasms, General Neuroscience, Spheroid, medicine.disease, 030104 developmental biology, Cell culture, 030220 oncology & carcinogenesis, Cancer research, Glioblastoma
Abstract

Two-dimensional (2D) cell cultures do not mimic in vivo tumor growth satisfactorily. Therefore, three-dimensional (3D) culture spheroid models were developed. These models may be particularly important in the field of neuro-oncology. Indeed, brain tumors have the tendency to invade the healthy brain environment. We describe herein an ideal 3D glioblastoma spheroid-based assay that we developed to study tumor invasion. We provide all technical details and analytical tools to successfully perform this assay.

Published
2020

11. Therapeutic implications of altered cholesterol homeostasis mediated by loss of CYP46A1 in human glioblastoma

Author

Halala Saed, Hrvoje Miletic, Frits Thorsen, Anjing Chen, Mingzhi Han, Thomas Daubon, Jian Wang, Xingang Li, Bin Huang, Zhao Wenbo, Shuai Wang, Ning Yang, Xu Wang, Rolf Bjerkvig, Gang Li, Shandong University, University of Bergen (UiB), Laboratoire Angiogenèse et Micro-environnement des Cancers (LAMC), Université Sciences et Technologies - Bordeaux 1-Institut National de la Santé et de la Recherche Médicale (INSERM), Haukeland University Hospital, Luxembourg Institute of Health (LIH), Université Sciences et Technologies - Bordeaux 1 (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM), and DAUBON, Thomas

Subjects
0301 basic medicine, Medicine (General), Regulator, [SDV.CAN]Life Sciences [q-bio]/Cancer, QH426-470, Article, cholesterol homeostasis, 03 medical and health sciences, chemistry.chemical_compound, R5-920, 0302 clinical medicine, [SDV.CAN] Life Sciences [q-bio]/Cancer, In vivo, Chemical Biology, Genetics, Cholesterol 24-Hydroxylase, Homeostasis, Humans, Medicine, 24OHC, Liver X receptor, Cancer, business.industry, Cell growth, Activator (genetics), Cholesterol, glioblastoma, Brain, efavirenz, Articles, 3. Good health, Sterol regulatory element-binding protein, CYP46A1, 030104 developmental biology, chemistry, Cancer research, Molecular Medicine, Ectopic expression, lipids (amino acids, peptides, and proteins), business, Glioblastoma, 030217 neurology & neurosurgery, Neuroscience
Abstract

Dysregulated cholesterol metabolism is a hallmark of many cancers, including glioblastoma (GBM), but its role in disease progression is not well understood. Here, we identified cholesterol 24‐hydroxylase (CYP46A1), a brain‐specific enzyme responsible for the elimination of cholesterol through the conversion of cholesterol into 24(S)‐hydroxycholesterol (24OHC), as one of the most dramatically dysregulated cholesterol metabolism genes in GBM. CYP46A1 was significantly decreased in GBM samples compared with normal brain tissue. A reduction in CYP46A1 expression was associated with increasing tumour grade and poor prognosis in human gliomas. Ectopic expression of CYP46A1 suppressed cell proliferation and in vivo tumour growth by increasing 24OHC levels. RNA‐seq revealed that treatment of GBM cells with 24OHC suppressed tumour growth through regulation of LXR and SREBP signalling. Efavirenz, an activator of CYP46A1 that is known to penetrate the blood–brain barrier, inhibited GBM growth in vivo. Our findings demonstrate that CYP46A1 is a critical regulator of cellular cholesterol in GBM and that the CYP46A1/24OHC axis is a potential therapeutic target., Loss of CYP46A1 partially caused excessive cholesterol accumulation in glioblastoma cells contributing to the maintenance of tumour cell viability and a malignant state. Efavirenz, an anti‐HIV drug, crosses the BBB and shows anti‐tumor effect though activation of the CYP46A1/24OHC axis.

Published
2019

12. The tumor organismal environment: Role in tumor development and cancer immunotherapy

Author

Lothar C. Dieterich, Andreas Bikfalvi, CCSD, Accord Elsevier, Eidgenössische Technische Hochschule - Swiss Federal Institute of Technology [Zürich] (ETH Zürich), Laboratoire Angiogenèse et Micro-environnement des Cancers (LAMC), Université Sciences et Technologies - Bordeaux 1 (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Université Sciences et Technologies - Bordeaux 1-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
0301 basic medicine, Cancer Research, medicine.medical_treatment, [SDV]Life Sciences [q-bio], Biology, 03 medical and health sciences, 0302 clinical medicine, Immune system, Cancer immunotherapy, Neoplasms, Tumor organismal environment, medicine, Tumor Microenvironment, Humans, Tumor growth, Tumor microenvironment, Cancer, Immunotherapy, medicine.disease, Macroenvironment, 3. Good health, [SDV] Life Sciences [q-bio], Haematopoiesis, 030104 developmental biology, Lymphatic system, Drug Resistance, Neoplasm, 030220 oncology & carcinogenesis, Cancer research
Abstract

International audience; Tumor immunotherapy has resulted in dramatic effects in some cancer types, including curing of previously untreatable patients. However, the response rates are typically very heterogenous, with some patients showing dramatic responses whereas others do not or only barely respond. Consequently, there has been an ever-increasing research effort to better understand the factors that govern immunotherapy responsiveness and efficiency in order to identify predictive biomarkers and novel therapeutic targets. Clearly, traits of the tumor cells as well as aspects of the tumor microenvironment (TME) play an important role in this regard. However, a growing tumor not only interacts with cells in its immediate vicinity, but also reciprocally communicates with the entire host organism (and its microbiota). Thus, systemic influences on tumor growth and progression are likely to be similarly important as the microenvironment. In this review, we focus on various aspects of the "tumor organismal environment" (TOE), namely the lymphatic, the hematopoietic, the microbial, the neurogenic and the metabolic environment, and discuss their impact on tumor growth and immunotherapy.

Published
2019

13. A model of guided cell self-organization for rapid and spontaneous formation of functional vessels

Author

Andrique, L., Recher, G., Alessandri, K., Pujol, N., Feyeux, M., Bon, P., Cognet, L., Nassoy, P., Bikfalvi, A., Laboratoire Angiogenèse et Micro-environnement des Cancers (LAMC), Université Sciences et Technologies - Bordeaux 1-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire Photonique, Numérique et Nanosciences (LP2N), Université de Bordeaux (UB)-Institut d'Optique Graduate School (IOGS)-Centre National de la Recherche Scientifique (CNRS), Université Sciences et Technologies - Bordeaux 1 (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM), Nassoy, Pierre, and Recher, Gaelle

Subjects
Alginates, [PHYS.PHYS.PHYS-BIO-PH]Physics [physics]/Physics [physics]/Biological Physics [physics.bio-ph], Myocytes, Smooth Muscle, Cell Line, Human Umbilical Vein Endothelial Cells, Humans, Vasoconstrictor Agents, Health and Medicine, Research Articles, ComputingMilieux_MISCELLANEOUS, Endothelin-1, Tissue Engineering, Tissue Scaffolds, [PHYS.PHYS.PHYS-BIO-PH] Physics [physics]/Physics [physics]/Biological Physics [physics.bio-ph], Models, Cardiovascular, SciAdv r-articles, Hydrogels, Microfluidic Analytical Techniques, Coculture Techniques, Extracellular Matrix, Drug Combinations, Vasoconstriction, cardiovascular system, Blood Vessels, Proteoglycans, Collagen, Endothelium, Vascular, Laminin, Research Article
Abstract

We develop a new in vitro model of vessel formation involving guided self-assembly of cellular components of the vascular wall., Most achievements to engineer blood vessels are based on multiple-step manipulations such as manual sheet rolling or sequential cell seeding followed by scaffold degradation. Here, we propose a one-step strategy using a microfluidic coextrusion device to produce mature functional blood vessels. A hollow alginate hydrogel tube is internally coated with extracellular matrix to direct the self-assembly of a mixture of endothelial cells (ECs) and smooth muscle cells (SMCs). The resulting vascular structure has the correct configuration of lumen, an inner lining of ECs, and outer sheath of SMCs. These “vesseloids” reach homeostasis within a day and exhibit the following properties expected for functional vessels (i) quiescence, (ii) perfusability, and (iii) contractility in response to vasoconstrictor agents. Together, these findings provide an original and simple strategy to generate functional artificial vessels and pave the way for further developments in vascular graft and tissue engineering and for deciphering the angiogenesis process.

Published
2019

14. Beyond the tumour microenvironment

Author

Dorothée Duluc, Lucie Laplane, Nicolas Larmonier, Thomas Pradeu, Andreas Bikfalvi, Hématopoïèse normale et pathologique (U1170 Inserm), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut d'Histoire et de Philosophie des Sciences et des Techniques (IHPST), Université Paris 1 Panthéon-Sorbonne (UP1)-Centre National de la Recherche Scientifique (CNRS), Immunology from Concept and Experiments to Translation (ImmunoConcept), Centre National de la Recherche Scientifique (CNRS)-Université de Bordeaux (UB), Mecanismes Moleculaires de l'Angiogenese, Université Sciences et Technologies - Bordeaux 1-Institut National de la Santé et de la Recherche Médicale (INSERM), Laplane, Lucie, Cellules souches hématopoïétiques et développement des hémopathies myéloïdes (CSHMyelo), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS), Université Sciences et Technologies - Bordeaux 1 (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)

Subjects
Cancer Research, Carcinogenesis, Mini Review, [SDV]Life Sciences [q-bio], education, microbiome, Antineoplastic Agents, [SHS.HISPHILSO]Humanities and Social Sciences/History, Philosophy and Sociology of Sciences, 03 medical and health sciences, 0302 clinical medicine, [SHS.HISPHILSO] Humanities and Social Sciences/History, Philosophy and Sociology of Sciences, Neoplasms, Tumor Microenvironment, medicine, Animals, Humans, ComputingMilieux_MISCELLANEOUS, Cognitive science, nervous system, Cancer, medicine.disease, Gastrointestinal Microbiome, 3. Good health, [SDV] Life Sciences [q-bio], Disease Models, Animal, immune system, Treatment Outcome, Oncology, 030220 oncology & carcinogenesis, Disease Progression, tumour organismal environment, sense organs, Cancer development, Erratum, tumour microenvironment
Abstract

In contrast to the once dominant tumour-centric view of cancer, increasing attention is now being paid to the tumour microenvironment (TME), generally understood as the elements spatially located in the vicinity of the tumour. Thinking in terms of TME has proven extremely useful, in particular because it has helped identify and comprehend the role of nongenetic and noncell-intrinsic factors in cancer development. Yet some current approaches have led to a TME-centric view, which is no less problematic than the former tumour-centric vision of cancer, insofar as it tends to overlook the role of components located beyond the TME, in the 'tumour organismal environment' (TOE). In this minireview, we highlight the explanatory and therapeutic shortcomings of the TME-centric view and insist on the crucial importance of the TOE in cancer progression.

Published
2019

15. Deciphering the complex role of thrombospondin-1 in glioblastoma development

Author

Thomas Daubon, Céline Léon, Kim Clarke, Laetitia Andrique, Laura Salabert, Elodie Darbo, Raphael Pineau, Sylvaine Guérit, Marlène Maitre, Stéphane Dedieu, Albin Jeanne, Sabine Bailly, Jean-Jacques Feige, Hrvoje Miletic, Marco Rossi, Lorenzo Bello, Francesco Falciani, Rolf Bjerkvig, Andréas Bikfalvi, University of Bergen (UiB), Laboratoire Angiogenèse et Micro-environnement des Cancers (LAMC), Université Sciences et Technologies - Bordeaux 1-Institut National de la Santé et de la Recherche Médicale (INSERM), University of Liverpool, Actions for OnCogenesis understanding and Target Identification in ONcology (ACTION), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Bordeaux Segalen - Bordeaux 2-Institut Bergonié [Bordeaux], UNICANCER-UNICANCER, Centre de Bioinformatique de Bordeaux (CBIB), CGFB, Université de Bordeaux (UB), INSERM, Neurocentre Magendie, U1215, Physiopathologie de la Plasticité Neuronale, F-33000 Bordeaux, France, Matrice extracellulaire et dynamique cellulaire - UMR 7369 (MEDyC), Université de Reims Champagne-Ardenne (URCA)-SFR CAP Santé (Champagne-Ardenne Picardie Santé), Université de Reims Champagne-Ardenne (URCA)-Université de Picardie Jules Verne (UPJV)-Université de Reims Champagne-Ardenne (URCA)-Université de Picardie Jules Verne (UPJV)-Centre National de la Recherche Scientifique (CNRS), Société d’Accélération du Transfert de Technologie (SATT NORD), Biologie du Cancer et de l'Infection (BCI ), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes (UGA), Haukeland University Hospital, Università degli Studi di Milano [Milano] (UNIMI), Luxembourg Institute of Health (LIH), Université Sciences et Technologies - Bordeaux 1 (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM), KG Jebsen Brain Tumor Research Center, Institut Bergonié [Bordeaux], UNICANCER-UNICANCER-Université Bordeaux Segalen - Bordeaux 2-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Bordeaux 1 - Sciences Technologies (U. Bordeaux 1), Neurocentre Magendie, Physiopathologie de la Plasticité Neuronale, U1215, Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Reims Champagne-Ardenne (URCA)-Université de Reims Champagne-Ardenne (URCA)-Centre National de la Recherche Scientifique (CNRS), Famille BMP dans l'angiogenèse et la lymphangiogenèse (BAL ), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Neurosurgical Oncology Unit, Department of Oncology and Hemato-Oncology, Humanitas Research Hospital, Neurosurgical Oncology Unit, Department of Oncology and Hemato-Oncology, Humanitas Research Hospital -Neurosurgical Oncology Unit, Department of Oncology and Hemato-Oncology, Humanitas Research Hospital, Neurocentre Magendie : Physiopathologie de la Plasticité Neuronale (U1215 Inserm - UB), Université de Bordeaux (UB)-Institut François Magendie-Institut National de la Santé et de la Recherche Médicale (INSERM), Università degli Studi di Milano = University of Milan (UNIMI), SFR CAP Santé (Champagne-Ardenne Picardie Santé), Université de Reims Champagne-Ardenne (URCA)-Université de Picardie Jules Verne (UPJV)-Université de Reims Champagne-Ardenne (URCA)-Université de Picardie Jules Verne (UPJV)-Université de Reims Champagne-Ardenne (URCA)-Centre National de la Recherche Scientifique (CNRS), and DAUBON, Thomas

Subjects
Male, Science, CD47 Antigen, [SDV.CAN]Life Sciences [q-bio]/Cancer, Laser Capture Microdissection, Article, Thrombospondin 1, Transforming Growth Factor beta1, Mice, [SDV.CAN] Life Sciences [q-bio]/Cancer, Cell Line, Tumor, Spheroids, Cellular, Animals, Humans, Neoplasm Invasiveness, Smad3 Protein, RNA, Small Interfering, lcsh:Science, Promoter Regions, Genetic, Cerebral Cortex, Mice, Knockout, Brain Neoplasms, Survival Analysis, Xenograft Model Antitumor Assays, Gene Expression Regulation, Neoplastic, lcsh:Q, Glioblastoma, Peptides, Protein Binding, Signal Transduction
Abstract

We undertook a systematic study focused on the matricellular protein Thrombospondin-1 (THBS1) to uncover molecular mechanisms underlying the role of THBS1 in glioblastoma (GBM) development. THBS1 was found to be increased with glioma grades. Mechanistically, we show that the TGFβ canonical pathway transcriptionally regulates THBS1, through SMAD3 binding to the THBS1 gene promoter. THBS1 silencing inhibits tumour cell invasion and growth, alone and in combination with anti-angiogenic therapy. Specific inhibition of the THBS1/CD47 interaction using an antagonist peptide decreases cell invasion. This is confirmed by CD47 knock-down experiments. RNA sequencing of patient-derived xenograft tissue from laser capture micro-dissected peripheral and central tumour areas demonstrates that THBS1 is one of the gene with the highest connectivity at the tumour borders. All in all, these data show that TGFβ1 induces THBS1 expression via Smad3 which contributes to the invasive behaviour during GBM expansion. Furthermore, tumour cell-bound CD47 is implicated in this process., Thrombospondin-1 (THSB1) is a component of the ECM with a role in regulating cancer development and tumour vasculature. Here, the authors show that TGF-beta-induced THBS1 expression contributes to the invasive behaviour of GBM cells and promotes resistance to antiangiogenic therapy partially through interaction with CD47.

Published
2019

16. Brain-Immune Interactions and Neuroinflammation After Traumatic Brain Injury

Author

Dinet, Virginie, Petry, Klaus, Badaut, Jerome, Laboratoire Angiogenèse et Micro-environnement des Cancers (LAMC), Université Sciences et Technologies - Bordeaux 1-Institut National de la Santé et de la Recherche Médicale (INSERM), Neuroinflammation: imagerie et thérapie de la sclérose en plaques, Université Bordeaux Segalen - Bordeaux 2-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de Neurosciences cognitives et intégratives d'Aquitaine (INCIA), Université Bordeaux Segalen - Bordeaux 2-Université Sciences et Technologies - Bordeaux 1-SFR Bordeaux Neurosciences-Centre National de la Recherche Scientifique (CNRS), Loma Linda University, Badaut, Jerome, Université Sciences et Technologies - Bordeaux 1 (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Université Bordeaux Segalen - Bordeaux 2-Université Sciences et Technologies - Bordeaux 1 (UB)-SFR Bordeaux Neurosciences-Centre National de la Recherche Scientifique (CNRS)

Subjects
astrocyte, [SDV.IMM] Life Sciences [q-bio]/Immunology, traumatic brain injury, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, [SDV.NEU.NB] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, [SDV.IMM]Life Sciences [q-bio]/Immunology, complement, blood-brain barrier, neuroinflammation
Abstract

International audience; Traumatic brain injury (TBI) is the principal cause of death and disability in children and young adults. Clinical and preclinical research efforts have been carried out to understand the acute, life-threatening pathophysiological events happening after TBI. In the past few years, however, it was recognized that TBI causes significant morbidity weeks, months, or years after the initial injury, thereby contributing substantially to the overall burden of TBI and the decrease of life expectancy in these patients. Long-lasting sequels of TBI include cognitive decline/dementia, sensory-motor dysfunction, and psychiatric disorders, and most important for patients is the need for socioeconomic rehabilitation affecting their quality of life. Cerebrovascular alterations have been described during the first week after TBI for direct consequence development of neuroinflammatory process in relation to brain edema. Within the brain-immune interactions, the complement system, which is a family of blood and cell surface proteins, participates in the pathophysiology process. In fact, the complement system is part of the primary defense and clearance component of innate and adaptive immune response. In this review, the complement activation after TBI will be described in relation to the activation of the microglia and astrocytes as well as the blood-brain barrier dysfunction during the first week after the injury. Considering the neuroinflammatory activity as a causal element of neurological handicaps, some major parallel lines of complement activity in multiple sclerosis and Alzheimer pathologies with regard to cognitive impairment will be discussed for chronic TBI. A better understanding of the role of complement activation could facilitate the development of new therapeutic approaches for TBI

Published
2019

17. The invasive proteome of glioblastoma revealed by laser-capture microdissection

Author

Daubon, Thomas, Guyon, Joris, Raymond, Anne-Aurélie, Dartigues, Benjamin, Rudewicz, Justine, Ezzoukhry, Zakaria, Dupuy, Jean-William, Herbert, John, Saltel, Frédéric, Bjerkvig, Rolf, Nikolski, Macha, Bikfalvi, Andreas, Nikolski, Macha, Laboratoire Angiogenèse et Micro-environnement des Cancers (LAMC), Université Sciences et Technologies - Bordeaux 1 (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM), University of Bergen (UiB), Transbiomed : Biologie Fondamentale et Appliquée à la Médecine, Université Bordeaux Segalen - Bordeaux 2-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre de Bioinformatique de Bordeaux (CBIB), CGFB, Centre Génomique Fonctionnelle Bordeaux [Bordeaux] (CGFB), Institut Polytechnique de Bordeaux-Université de Bordeaux Ségalen [Bordeaux 2], Disease Gene Discovery Limited [London, UK], Bordeaux Research In Translational Oncology [Bordeaux] (BaRITOn), Université de Bordeaux (UB)-CHU Bordeaux [Bordeaux]-Institut National de la Santé et de la Recherche Médicale (INSERM), KG Jebsen Brain Tumor Research Center, Laboratoire Bordelais de Recherche en Informatique (LaBRI), Université de Bordeaux (UB)-École Nationale Supérieure d'Électronique, Informatique et Radiocommunications de Bordeaux (ENSEIRB)-Centre National de la Recherche Scientifique (CNRS), Université Sciences et Technologies - Bordeaux 1-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Bordeaux Segalen - Bordeaux 2-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS)-École Nationale Supérieure d'Électronique, Informatique et Radiocommunications de Bordeaux (ENSEIRB), Centre de recherche en pharmacologie - santé (CRPS), Centre National de la Recherche Scientifique (CNRS), Institut de pharmacologie et de biologie structurale (IPBS), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Biologie Moléculaire de la Cellule (LBMC), École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), and Centre National de la Recherche Scientifique (CNRS)-École Nationale Supérieure d'Électronique, Informatique et Radiocommunications de Bordeaux (ENSEIRB)-Université Sciences et Technologies - Bordeaux 1-Université Bordeaux Segalen - Bordeaux 2

Subjects
patient-derived xenograft, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, proteomics analysis, glioblastoma, [SDV.NEU.NB] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, intratumor heterogeneity, [SDV.CAN]Life Sciences [q-bio]/Cancer, invasion, [SDV.CAN] Life Sciences [q-bio]/Cancer, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Basic and Translational Investigations, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], [INFO.INFO-BI]Computer Science [cs]/Bioinformatics [q-bio.QM], ComputingMilieux_MISCELLANEOUS
Abstract

International audience; Background. Glioblastomas are heterogeneous tumors composed of a necrotic and tumor core and an invasive periphery.Methods. Here, we performed a proteomics analysis of laser-capture micro-dissected glioblastoma core and invasive areas of patient-derived xenografts.Results. Bioinformatics analysis identified enriched proteins in central and invasive tumor areas. Novel markers of invasion were identified, the genes proteolipid protein 1 (PLP1) and Dynamin-1 (DNM1), which were subsequently validated in tumors and by functional assays.Conclusions. In summary, our results identify new networks and molecules that may play an important role in glioblastoma development and may constitute potential novel therapeutic targets.

Published
2019

18. Deciphering the complex role of thrombospondin-1 in glioblastoma development

Author

Daubon, Thomas, Léon, Céline, Clarke, Kim, Andrique, Laëtitia, Salabert, Laura, Darbo, Elodie, Pineau, Raphäel, Guérit, Sylvaine, Maitre, Marlène, Dedieu, Stéphane, Jeanne, Albin, Bailly, Sabine, Feige, Jean-Jacques, Miletic, Hrvoje, Rossi, Marco, Bello, Lorenzo, Falciani, Francesco, Bjerkvig, Rolf, Bikfalvi, Andreas, Feige, Jean-Jacques, Laboratoire Angiogenèse et Micro-environnement des Cancers (LAMC), Université Sciences et Technologies - Bordeaux 1 (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM), KG Jebsen Brain Tumor Research Center, University of Liverpool, Actions for OnCogenesis understanding and Target Identification in ONcology (ACTION), Institut Bergonié [Bordeaux], UNICANCER-UNICANCER-Université Bordeaux Segalen - Bordeaux 2-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Bordeaux 1 - Sciences Technologies (U. Bordeaux 1), Neurocentre Magendie, Physiopathologie de la Plasticité Neuronale, U1215, Institut National de la Santé et de la Recherche Médicale (INSERM), Matrice extracellulaire et dynamique cellulaire - UMR 7369 (MEDyC), Université de Reims Champagne-Ardenne (URCA)-SFR CAP Santé (Champagne-Ardenne Picardie Santé), Université de Reims Champagne-Ardenne (URCA)-Université de Picardie Jules Verne (UPJV)-Université de Reims Champagne-Ardenne (URCA)-Université de Picardie Jules Verne (UPJV)-Centre National de la Recherche Scientifique (CNRS), Famille BMP dans l'angiogenèse et la lymphangiogenèse (BAL ), Biologie du Cancer et de l'Infection (BCI ), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Neurosurgical Oncology Unit, Department of Oncology and Hemato-Oncology, Humanitas Research Hospital, and Neurosurgical Oncology Unit, Department of Oncology and Hemato-Oncology, Humanitas Research Hospital -Neurosurgical Oncology Unit, Department of Oncology and Hemato-Oncology, Humanitas Research Hospital

Subjects
[SDV.CAN] Life Sciences [q-bio]/Cancer, [SDV.CAN]Life Sciences [q-bio]/Cancer
Abstract

International audience; We undertook a systematic study focused on the matricellular protein Thrombospondin-1 (THBS1) to uncover molecular mechanisms underlying the role of THBS1 in glioblastoma (GBM) development. THBS1 was found to be increased with glioma grades. Mechanistically, we show that the TGFβ canonical pathway transcriptionally regulates THBS1, through SMAD3 binding to the THBS1 gene promoter. THBS1 silencing inhibits tumour cell invasion and growth, alone and in combination with anti-angiogenic therapy. Specific inhibition of the THBS1/CD47 interaction using an antagonist peptide decreases cell invasion. This is confirmed by CD47 knock-down experiments. RNA sequencing of patient-derived xenograft tissue from laser capture micro-dissected peripheral and central tumour areas demonstrates that THBS1 is one of the gene with the highest connectivity at the tumour borders. All in all, these data show that TGFβ1 induces THBS1 expression via Smad3 which contributes to the invasive behaviour during GBM expansion. Furthermore, tumour cell-bound CD47 is implicated in this process.

Published
2019

19. 3D chemical imaging of brain tumors

Author

Ogunleke, Abiodun, STAR, ABES, Laboratoire Angiogenèse et Micro-environnement des Cancers (LAMC), Université Sciences et Technologies - Bordeaux 1 (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Bordeaux, and Cyril Petibois

Subjects
[CHIM.THEO]Chemical Sciences/Theoretical and/or physical chemistry, [CHIM.THEO] Chemical Sciences/Theoretical and/or physical chemistry, Imagerie IR-QCL, Digital pathology, FTIR microscopy, Imagerie IRTF, Imagerie chimique 3D, Clinical test, Pathologie numérique, Test clinique, QCL-IR imaging, 3D chemical imaging
Abstract

Three-dimensional (3D) histology is a new advanced tool for cancerology. The whole chemical profile and physiological characteristics of a tissue is essential to understand the rationale of pathology development. However, there is no analytical technique, in vivo or histological, that is able to discover such abnormal features and provide a 3D distribution at microscopic resolution.Here, we introduce a unique high- throughput infrared (IR) microscopy method that combines automated image correction and subsequent spectral data analysis for 3D-IR image reconstruction. I performed spectral analysis of a complete organ for a small animal model, a mouse brain with animplanted glioma tumor. The 3D-IR image is reconstructed from 370 consecutive tissue sectionsand corrected using the X-ray tomogram of the organ for an accurate quantitative analysis of thechemical content. A 3D matrix of 89 x 106 IR spectra is generated, allowing us to separate the tumor mass from healthy brain tissues based on various anatomical, chemical, and metabolic parameters. I demonstrate for the first time that quantitative metabolic parameters (glucose, glycogen and lactate) can be extracted and reconstructed in 3D from the IR spectra for the characterization of the brain vs. tumor metabolism (assessing the Warburg effect in tumors). Our method can be further exploited by searching for the whole spectral profile, discriminating different anatomical landmarks in the brain. I demonstrate this by the reconstruction of the corpus callosum and basal ganglia region of the brain., L'histologie tridimensionnelle (3D) est un nouvel outil avancé de cancérologie. L'ensemble du profil chimique et des caractéristiques physiologiques d'un tissu est essentiel pour comprendre la logique du développement d'une pathologie. Cependant, il n'existe aucune technique analytique, in vivo ou histologique, capable de découvrir de telles caractéristiques anormales et de fournir une distribution3D à une résolution microscopique. Nous présentons ici une méthode unique de microscopie infrarouge (IR) à haut débit combinant une correction d'image automatisée et une analyse ultérieure des données spectrales pour la reconstruction d'image 3D-IR. Nous avons effectué l'analyse spectrale d'un organe complet pour un petit modèle animal, un cerveau de souris avec une tumeur de gliome implantée. L'image 3D-IR est reconstruite à partir de 370 coupes de tissus consécutives et corrigée à l'aide du tomogramme à rayons X de l'organe pour une analyse quantitative précise du contenu chimique. Une matrice 3D de spectres IR 89 x 106 est générée, ce qui nous permet de séparer la masse tumorale des tissus cérébraux sains en fonction de divers paramètres anatomiques,chimiques et métaboliques. Nous démontrons pour la première fois que des paramètres métaboliques quantitatifs (glucose, glycogène et lactate) peuvent être extraits et reconstruits en 3D à partir des spectres IR pour la caractérisation du métabolisme cérébral / tumoral (évaluation de l'effet de Warburg dans les tumeurs). Notre méthode peut être davantage exploitée en recherchant l'ensemble du profil spectral, en distinguant différents points de repère anatomiques dans le cerveau.Nous le démontrons par la reconstruction du corps calleux et de la région des noyaux gris centraux du cerveau.

Published
2019

20. Patients Lung Derived Tumoroids (PLDTs) to model therapeutic response

Author

Delphine Fessart, Geraldine Siegfried, Jacques Robert, Hugues Begueret, Abdel-Majid Khatib, Fabienne Soulet, Thomas Grenier, Inaki Begiristain, Frédéric Delom, Actions for OnCogenesis understanding and Target Identification in ONcology (ACTION), Institut Bergonié [Bordeaux], UNICANCER-UNICANCER-Université Bordeaux Segalen - Bordeaux 2-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire Angiogenèse et Micro-environnement des Cancers (LAMC), Université Sciences et Technologies - Bordeaux 1-Institut National de la Santé et de la Recherche Médicale (INSERM), Chemistry, Oncogenesis, Stress and Signaling (COSS), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-CRLCC Eugène Marquis (CRLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM), CRLCC Eugène Marquis (CRLCC), UNICANCER, This work was supported by grants from the 'Région Nouvelle-Aquitaine'. FD was supported by grants from the 'Fondation ARC pour la Recherche sur le Cancer'. DF has been supported by the 'Agence Nationale de la Recherche (ANR)'. TG was supported by the 'SIRIC Brio'., Université Sciences et Technologies - Bordeaux 1 (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Rennes (UR)-CRLCC Eugène Marquis (CRLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Jonchère, Laurent

Subjects
0301 basic medicine, Oncology, Drug, medicine.medical_specialty, Lung Neoplasms, media_common.quotation_subject, Primary Cell Culture, [SDV.CAN]Life Sciences [q-bio]/Cancer, Mice, 03 medical and health sciences, 0302 clinical medicine, [SDV.CAN] Life Sciences [q-bio]/Cancer, Cell Line, Tumor, Internal medicine, Tumor Microenvironment, medicine, Animals, Humans, Lung cancer, Lung, Molecular Biology, media_common, Tumor microenvironment, Radiation, business.industry, Cell Biology, medicine.disease, Precision medicine, Xenograft Model Antitumor Assays, Anticancer drug, Three-dimensional culture, 3. Good health, Tumoroids, 030104 developmental biology, medicine.anatomical_structure, Lung cancer cell, 030220 oncology & carcinogenesis, Chemotherapeutic drugs, Drug Screening Assays, Antitumor, business, Ex vivo
Abstract

International audience; Preclinical lung cancer models are essential for a basic understanding of lung cancer biology and its translation into efficient treatment options for affected patients. Lung cancer cell lines and xenografts derived directly from human lung tumors have proven highly valuable in fundamental oncology research and anticancer drug discovery. Both models inherently comprise advantages and caveats that have to be accounted for. Recently, we have enabled reliable in vitro culture techniques from lung cancer biopsies as Patients Lung Derived Tumoroids (PLDTs). This breakthrough provides the possibility of high-throughput drug screening covering the spectrum of lung cancer phenotypes seen clinically. We have adapted and optimized our in vitro three-dimensional model as a preclinical lung cancer model to recapitulate the tumor microenvironment (TME) using matrix reconstitution. Hence, we developed directly PLDTs to screen for chemotherapeutics and radiation treatment. This original model will enable precision medicine to become a reality, allowing a given patient sample to be screened for effective ex vivo therapeutics, aiming at tailoring of treatments specific to that individual. Hence, this tool can enhance clinical outcomes and avoid morbidity due to ineffective therapies.

Published
2020

21. The Multiple Layers of the Tumor Environment

Author

Nicolas Larmonier, Lucie Laplane, Andreas Bikfalvi, Thomas Pradeu, Dorothée Duluc, Institut d'Histoire et de Philosophie des Sciences et des Techniques (IHPST), Université Paris 1 Panthéon-Sorbonne (UP1)-Département d'Etudes Cognitives - ENS Paris (DEC), École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS), Immunology from Concept and Experiments to Translation (ImmunoConcept), Centre National de la Recherche Scientifique (CNRS)-Université de Bordeaux (UB), Laboratoire Angiogenèse et Micro-environnement des Cancers (LAMC), Université Sciences et Technologies - Bordeaux 1-Institut National de la Santé et de la Recherche Médicale (INSERM), European Project: 637647,H2020,ERC-2014-STG,IDEM(2015), École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS-PSL), Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS), Université Sciences et Technologies - Bordeaux 1 (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hématopoïèse normale et pathologique (U1170 Inserm), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR), Université Panthéon-Sorbonne (UP1)-Centre National de la Recherche Scientifique (CNRS)-Département d'Etudes Cognitives - ENS Paris (DEC), École normale supérieure - Paris (ENS Paris)-École normale supérieure - Paris (ENS Paris), Steele Children's Research Center, University of Arizona, and Mecanismes Moleculaires de l'Angiogenese

Subjects
0301 basic medicine, tumor organismal environment, Cancer Research, Angiogenesis, [SDV]Life Sciences [q-bio], [SDV.CAN]Life Sciences [q-bio]/Cancer, Computational biology, Biology, [SHS]Humanities and Social Sciences, [SHS.HISPHILSO]Humanities and Social Sciences/History, Philosophy and Sociology of Sciences, 03 medical and health sciences, angiogenesis, Neoplasms, medicine, Humans, [SDV.BDD]Life Sciences [q-bio]/Development Biology, [SDV.EE]Life Sciences [q-bio]/Ecology, environment, Tumor microenvironment, [SHS.PHIL]Humanities and Social Sciences/Philosophy, Cancer, medicine.disease, Combined Modality Therapy, 3. Good health, niche, immune system, 030104 developmental biology, Oncology, Disease Progression, Neoplastic Stem Cells, [SDV.IMM]Life Sciences [q-bio]/Immunology, sense organs, Construct (philosophy)
Abstract

International audience; The notion of tumor microenvironment (TME) has been brought to the forefront of recent scientific literature on cancer. However, there is no consensus on how to define and spatially delineate the TME. We propose that the time is ripe to go beyond an all-encompassing list of the components of the TME, and to construct a multilayered view of cancer. We distinguish six layers of environmental interactions with the tumor and show that they are associated with distinct mechanisms, and ultimately with distinct therapeutic approaches.

Published
2018
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22. Blockade of the malignant phenotype by β-subunit selective noncovalent inhibition of immuno- and constitutive proteasomes

Author

Villoutreix, Bruno O., Khatib, Abdel-Majid, Cheng, Yan, Miteva, Maria A., Maréchal, Xavier, Vidal, Joëlle, Reboud-Ravaux, Michèle, Molécules Thérapeutiques in silico (MTI), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire Angiogenèse et Micro-environnement des Cancers (LAMC), Université Sciences et Technologies - Bordeaux 1 (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM), Adaptation Biologique et Vieillissement = Biological Adaptation and Ageing (B2A), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut des Sciences Chimiques de Rennes (ISCR), Université de Rennes (UR)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Ecole Nationale Supérieure de Chimie de Rennes (ENSCR)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Université Sciences et Technologies - Bordeaux 1-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Ecole Nationale Supérieure de Chimie de Rennes (ENSCR)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées (INSA), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Centre National de la Recherche Scientifique (CNRS)-Ecole Nationale Supérieure de Chimie de Rennes-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées (INSA)-Ecole Nationale Supérieure de Chimie de Rennes (ENSCR)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), and VIDAL, Joëlle

Subjects
immunoproteasome, [SDV.BIBS] Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], proteasomes, [SDV.CAN] Life Sciences [q-bio]/Cancer, [CHIM.THER] Chemical Sciences/Medicinal Chemistry, noncovalent inhibitors, [SDV.CAN]Life Sciences [q-bio]/Cancer, [CHIM.THER]Chemical Sciences/Medicinal Chemistry, piperazine, virtual screening, [SDV.BIBS]Life Sciences [q-bio]/Quantitative Methods [q-bio.QM]
Abstract

International audience; A structure-based virtual screening of over 400,000 small molecules against the constitutive proteasome activity followed by in vitro assays led to the discovery of a family of proteasome inhibitors with a sulfonyl piperazine scaffold. Some members of this family of small non-peptidic inhibitors were found to act selectively on the β2 trypsin-like catalytic site with a preference for the immunoproteasome β2i over the constitutive proteasome β2c, while some act on the β5 site and post-acid site β1 of both, the immunoproteasome and the constitutive proteasome. Anti-proliferative and anti-invasive effects on tumor cells were investigated and observed for two compounds. We report novel chemical inhibitors able to interfere with the three types of active centers of both, the immuno- and constitutive proteasomes. Identifying and analyzing a novel scaffold with decorations able to shift the binders’ active site selectivity is essential to design a future generation of proteasome inhibitors able to distinguish the immunoproteasome from the constitutive proteasome.

Published
2017

23. The role of CXCR3/LRP1 cross-talk in the invasion of primary brain tumors

Author

Boyé, K, Pujol, N, D Alves, I, Chen, YP, Daubon, T, Lee, YZ, Dedieu, S, Constantin, M, Bello, L, Rossi, M, Bjerkvig, R, Sue, SC, Bikfalvi, A, Billottet, C., Laboratoire Angiogenèse et Micro-environnement des Cancers (LAMC), Université Sciences et Technologies - Bordeaux 1-Institut National de la Santé et de la Recherche Médicale (INSERM), Chimie et Biologie des Membranes et des Nanoobjets (CBMN), Université de Bordeaux (UB)-École Nationale d'Ingénieurs des Travaux Agricoles - Bordeaux (ENITAB)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), National Tsing Hua University [Hsinchu] (NTHU), University of Bergen (UiB), Luxembourg Institute of Health (LIH), Matrice extracellulaire et dynamique cellulaire - UMR 7369 (MEDyC), SFR CAP Santé (Champagne-Ardenne Picardie Santé), Université de Reims Champagne-Ardenne (URCA)-Université de Picardie Jules Verne (UPJV)-Université de Reims Champagne-Ardenne (URCA)-Université de Picardie Jules Verne (UPJV)-Université de Reims Champagne-Ardenne (URCA)-Centre National de la Recherche Scientifique (CNRS), Università degli Studi di Milano [Milano] (UNIMI), DAUBON, Thomas, Université Sciences et Technologies - Bordeaux 1 (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Reims Champagne-Ardenne (URCA)-SFR CAP Santé (Champagne-Ardenne Picardie Santé), Université de Reims Champagne-Ardenne (URCA)-Université de Picardie Jules Verne (UPJV)-Université de Reims Champagne-Ardenne (URCA)-Université de Picardie Jules Verne (UPJV)-Centre National de la Recherche Scientifique (CNRS), Università degli Studi di Milano = University of Milan (UNIMI), and École Nationale d'Ingénieurs des Travaux Agricoles - Bordeaux (ENITAB)-Institut de Chimie du CNRS (INC)-Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Male, Receptors, CXCR3, Science, [SDV]Life Sciences [q-bio], Chick Embryo, Article, Mice, stomatognathic system, immune system diseases, Cell Movement, Spheroids, Cellular, Tumor Cells, Cultured, Animals, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Neoplasm Invasiveness, lcsh:Science, skin and connective tissue diseases, ComputingMilieux_MISCELLANEOUS, Mice, Knockout, Brain Neoplasms, Cell Membrane, hemic and immune systems, [SDV] Life Sciences [q-bio], Gene Expression Regulation, Neoplastic, stomatognathic diseases, Protein Transport, HEK293 Cells, lcsh:Q, Glioblastoma, Low Density Lipoprotein Receptor-Related Protein-1, Protein Binding
Abstract

CXCR3 plays important roles in angiogenesis, inflammation, and cancer. However, the precise mechanism of regulation and activity in tumors is not well known. We focused on CXCR3-A conformation and on the mechanisms controlling its activity and trafficking and investigated the role of CXCR3/LRP1 cross talk in tumor cell invasion. Here we report that agonist stimulation induces an anisotropic response with conformational changes of CXCR3-A along its longitudinal axis. CXCR3-A is internalized via clathrin-coated vesicles and recycled by retrograde trafficking. We demonstrate that CXCR3-A interacts with LRP1. Silencing of LRP1 leads to an increase in the magnitude of ligand-induced conformational change with CXCR3-A focalized at the cell membrane, leading to a sustained receptor activity and an increase in tumor cell migration. This was validated in patient-derived glioma cells and patient samples. Our study defines LRP1 as a regulator of CXCR3, which may have important consequences for tumor biology., The chemokine receptor CXCR3-A is expressed in high grade glioma. Here the authors show that CXCR3-A interacts with LPR1, a protein highly expressed in glioma, and this interaction regulates the trafficking of the receptor ultimately impacting on tumour cell migration.

Published
2017

24. Maturation protéolytique par les proprotéines convertases (PCs) dans l'angiogenèse, l'oncogenèse et l'infection virale : identification et étude de deux substrats des PCs

Author

Demoures, Béatrice, Laboratoire Angiogenèse et Micro-environnement des Cancers (LAMC), Université Sciences et Technologies - Bordeaux 1 (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Bordeaux, Abdel-Majid Khatib, and STAR, ABES

Subjects
viruses, Apeline, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Metastases, Proprotein convertases, Colorectal cancer, Cancer colorectal, GlycoprotéineB, Proteolytic maturation, Glycoprotein B, Apelin, Proprotéines convertases, Maturation protéolytique, Epstein-Barr Virus, Métastases, [SDV.BC] Life Sciences [q-bio]/Cellular Biology
Abstract

Proprotein convertases (PCs) are enzymes involved in many pathological processes. We have identified two novel substrates of the PCs: apelin and glycoprotein B (gB) of Epstein Barr Virus (EBV), and studied the role of PC-mediated proteolytic maturation in their functions. Apelin is overexpressed in some cancers including colorectal cancer (CRC), and we demonstrated that furin, one of the PCs member, cleaves apelin in two peptides. To determine the role of apelin cleavage by furin in the metastatic CRC, we generated a non-cleavable mutant (apelin-DM). This mutant inhibited the growth of colon cancer cells in vitro and could not protect against apoptosis, unlike the wild-type apelin. In vivo, apelin-DM drastically reduces tumor growth and the formation of hepatic metastases in mice. These results were confirmed in apelin deficient mouse models thus demonstrating the potential interest of using apelin-DM, or its derivatives, as anticancer agents in the treatment of metastatic CRC. The gB of EBV, a virus involved in some lymphoid and epithelial cancers in humans, is involved in the entry of the virus into the cell during infection. We have shown that PCs, especially furin, cleave gB. In vitro,induction of the LMP1 viral protein increases furin expression, which results in an increase in EBV infection. These results suggest the existence of a regulatory loop between furin and LMP1 to improve the cellular propagation of the virus. The use of inhibitors of PCs activity would thus block EBV infection, a virus against which there is no treatment nowadays., Les proprotéines convertases (PCs) sont des enzymes impliquées de nombreux processus pathologiques. Nous avons étudié deux substrats des PCs: l'apeline et la glycoprotéine B (gB) du virus d'Epstein Barr (EBV), et le rôle de cette maturation protéolytique dans la médiation de leurs fonctions. L'apeline est surexprimée dans plusieurs cancers dont le cancer colorectal (CCR), et nous avons montré que la furine, un membre des PCs, clive l’apeline. Pour déterminer le rôle de ce clivage dans le CCR métastatique, nous avons généré un mutant non clivable (apeline-DM). In vitro, ce mutant inhibe la croissance de cellules cancéreuses du côlonet ne les protège pas de l'apoptose, contrairement à l'apeline sauvage. In vivo, l'apeline-DM diminue drastiquement la croissance tumorale et la formation de métastases hépatiques chez la souris. Les mêmes résultats sont obtenus dans des modèles de souris déficientes pour l’apeline, démontrant l'intérêt d'utiliser l'apeline-DM ou des dérivés comme potentiels agents anticancéreux dans le traitement des CCR métastatiques. La gB du virus EBV, virus impliqué dans certains cancers lymphoïdes et épithéliaux chez l'homme, permet l'entrée du virus dans la cellule lors de l'infection. Nous avons montré que les PCs, et notamment la furine, clivent la gB. In vitro, l'induction de la protéine virale LMP1 augmente l'expression de la furine, qui se traduit par une augmentation de l'infection par EBV. Ces résultats suggèrent l'existence d'une boucle de régulation entre la furine et LMP1 permettant d'améliorer la propagation cellulaire du virus. L'utilisation d'inhibiteurs de l'activité des PCs permettrait donc de bloquer l'infection par EBV.

Published
2016

25. CD154 Induces Matrix Metalloproteinase-9 Secretion in Human Podocytes

Author

Rigothier, Claire, Daculsi, Richard, Lepreux, Sébastien, Auguste, Patrick, Villeneuve, Julien, Dewitte, Antoine, Doudnikoff, Evelyne, Saleem, Moin, Bourget, Chantal, Combe, Christian, Ripoche, Jean, Bioingénierie tissulaire (BIOTIS), Université de Bordeaux (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Néphrologie-transplantation-dialyse [Bordeaux], CHU Bordeaux [Bordeaux], Laboratoire Angiogenèse et Micro-environnement des Cancers (LAMC), Université Sciences et Technologies - Bordeaux 1 (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM), Howard Hughes Medical Institute (HHMI), Department of Molecular & Cell Biology [Berkeley], University of California [Berkeley] (UC Berkeley), University of California (UC)-University of California (UC), Centre for Genomic Regulation [Barcelona] (CRG), Universitat Pompeu Fabra [Barcelona] (UPF)-Centro Nacional de Analisis Genomico [Barcelona] (CNAG), Institut des Maladies Neurodégénératives [Bordeaux] (IMN), Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS), University of Bristol [Bristol], Service de Néphrologie-Transplantation-Dialyse, CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin, Chassande, Olivier, Université Sciences et Technologies - Bordeaux 1-Institut National de la Santé et de la Recherche Médicale (INSERM), University of California [Berkeley], and University of California-University of California

Subjects
Blood Platelets, Podocytes, Reverse Transcriptase Polymerase Chain Reaction, [SDV]Life Sciences [q-bio], Blotting, Western, CD40 Ligand, Cell Differentiation, hemic and immune systems, Real-Time Polymerase Chain Reaction, [SDV] Life Sciences [q-bio], Matrix Metalloproteinase 9, Humans, RNA, Messenger, CD40 Antigens, Cells, Cultured, Cell Proliferation
Abstract

Matrix remodeling is a key feature of glomerulosclerosis secondary to diabetes or hypertension. Podocytes contribute to glomerular basement membrane (GBM) turnover by producing matrix components and matrix remodelling enzymes, including matrix metalloproteinases (MMPs). The CD40/CD154 signaling pathway modulates matrix remodeling through the synthesis of MMPs and tissue inhibitors of MMPs. Platelets are a primary blood reservoir of CD154. Here we studied, the impact of the CD154/CD40 pathway on MMP-9 expression by cultured human podocytes. The role of CD40/CD154 was evaluated upon exposure of podocytes to recombinant human CD154 (rhCD154) or activated platelet supernatants from healthy human subjects. We first showed by protein and mRNA expression that CD40 was synthesized by podocytes and detectable on kidney tissue sections. CD40 expression was acquired during podocyte differentiation and enhanced upon exposure to rhCD154. In podocytes, rhCD154 induced an increase of MMP-9 production as shown by RT-PCR, Western blot and and gelatin zymography. Activated platelet supernatants induced MMP-9 mRNA synthesis in podocytes, an effect reduced by anti-CD40 antibody. Our results underscore a potential role for platelets through the CD40/CD154 signaling pathway in the control of GBM synthesis and degradation, via its regulatory role on MMP-9 production. CD154 secretion by activated platelets may contribute to GBM alterations in proteinuric nephropathies. J. Cell. Biochem. 117: 2737-2747, 2016. © 2016 Wiley Periodicals, Inc.

Published
2016

26. Secretion of protein disulphide isomerase AGR2 confers tumorigenic properties

Author

Tony Avril, Delphine Fessart, Raphael Pineau, Hugues Begueret, Eric Chevet, Carlo Lucchesi, Camille Malrieux, Charlotte Domblides, Leif A. Eriksson, Frédéric Delom, Nathalie Dugot-Senant, Centre de recherche Cardio-Thoracique de Bordeaux [Bordeaux] (CRCTB), Université Bordeaux Segalen - Bordeaux 2-CHU Bordeaux [Bordeaux]-Institut National de la Santé et de la Recherche Médicale (INSERM), Oncogenesis Stress Signaling (OSS), Université de Rennes (UR)-CRLCC Eugène Marquis (CRLCC), Université de Bordeaux (UB), CRLCC Eugène Marquis (CRLCC), Dept Chem & Mol Biol, University of Gothenburg (GU), Hôpital Haut-Lévêque [CHU Bordeaux], CHU Bordeaux [Bordeaux], Laboratoire Angiogenèse et Micro-environnement des Cancers (LAMC), Université Sciences et Technologies - Bordeaux 1 (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Bergonié [Bordeaux], UNICANCER, Pathologies infectieuses et cancers : aspects biologiques et thérapeutiques (PICABT), UNICANCER-UNICANCER-Université Bordeaux Segalen - Bordeaux 2-CHU Bordeaux [Bordeaux]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Ligue Contre le Cancer, Institut National Du Cancer [INCa₅869], Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-CRLCC Eugène Marquis (CRLCC), Université Sciences et Technologies - Bordeaux 1-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Bordeaux Segalen - Bordeaux 2-CHU Bordeaux [Bordeaux]-Institut Bergonié [Bordeaux], and UNICANCER-UNICANCER-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)

Subjects
0301 basic medicine, cell-proliferation, Mouse, Carcinogenesis, Regulator, migration, localization, Extracellular matrix, Mucoproteins, Neoplasms, pancreatic-cancer, Biology (General), anterior gradient-2, Cells, Cultured, organoids, Cancer Biology, Epithelial polarity, Oncogene Proteins, General Neuroscience, General Medicine, Extracellular Matrix, 3. Good health, endoplasmic reticulum, Biochemistry, Medicine, Research Article, AGR2, Human, QH301-705.5, Science, Morphogenesis, epithelial-mesenchymal transition, [SDV.CAN]Life Sciences [q-bio]/Cancer, Biology, survival, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, protein disulphide isomerase, Extracellular, Humans, cancer, metastasis, Secretion, extracellular-matrix, General Immunology and Microbiology, Endoplasmic reticulum, Proteins, Epithelial Cells, tissue, Cell Biology, 030104 developmental biology
Abstract

The extracellular matrix (ECM) plays an instrumental role in determining the spatial orientation of epithelial polarity and the formation of lumens in glandular tissues during morphogenesis. Here, we show that the Endoplasmic Reticulum (ER)-resident protein anterior gradient-2 (AGR2), a soluble protein-disulfide isomerase involved in ER protein folding and quality control, is secreted and interacts with the ECM. Extracellular AGR2 (eAGR2) is a microenvironmental regulator of epithelial tissue architecture, which plays a role in the preneoplastic phenotype and contributes to epithelial tumorigenicity. Indeed, eAGR2, is secreted as a functionally active protein independently of its thioredoxin-like domain (CXXS) and of its ER-retention domain (KTEL), and is sufficient, by itself, to promote the acquisition of invasive and metastatic features. Therefore, we conclude that eAGR2 plays an extracellular role independent of its ER function and we elucidate this gain-of-function as a novel and unexpected critical ECM microenvironmental pro-oncogenic regulator of epithelial morphogenesis and tumorigenesis. DOI: http://dx.doi.org/10.7554/eLife.13887.001, eLife digest Cancer cells multiply abnormally fast and therefore produce protein molecules faster than normal cells. To avoid becoming stressed by this overproduction, cancer cells make use of proteins that fold the new proteins inside the cell. One of these protein folders is called anterior gradient-2 (or AGR2 for short) and is produced at high levels in so-called epithelial cancers, such as breast and lung cancer. Previous research has shown that AGR2 inside cancer cells can help them grow and survive and AGR2 can also be found outside cells, such as in the blood or the urine of cancer patients. Therefore some researchers have suggested that measuring the levels of AGR2 in bodily fluids may be a useful marker for detecting cancers. Fessart et al. hypothesized that – apart from becoming a promising diagnostic tool – the AGR2 protein itself, specifically when found outside cells, might make cancer cells more aggressive. Fessart et al. used a range of techniques to test this hypothesis. For example, healthy lung cells and lung cancer cells were grown into miniature replicas of lung organs in the laboratory, and in a key experiment, AGR2 was added to the lung organoids grown from the healthy cells. The addition of AGR2 protein was enough to change the non-tumor organoids into tumor organoids and boosted their growth about ten-fold. Further experiments then revealed that AGR2 also makes cells more invasive and capable of moving, both important features of aggressive cancer cells. Overall, Fessart et al. have proven that AGR2 is a signalling molecule found outside cancer cells that makes them more aggressive. In future, more research addressing how AGR2 achieves this may lead to new therapeutic strategies against some forms of cancer. DOI: http://dx.doi.org/10.7554/eLife.13887.002

Published
2016

27. Glioblastoma invasion and cooption depend on IRE1α endoribonuclease activity

Author

Jabouille, Arnaud, Delugin, Maylis, Pineau, Raphäel, Dubrac, Alexandre, Soulet, Fabienne, Lhomond, Stéphanie, Pallares-Lupon, Nestor, Prats, Hervé, Bikfalvi, Andreas, Chevet, Eric, Touriol, Christian, Moenner, Michel, Laboratoire Angiogenèse et Micro-environnement des Cancers (LAMC), Université Sciences et Technologies - Bordeaux 1-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Composantes innées de la réponse immunitaire et différenciation (CIRID), Université Bordeaux Segalen - Bordeaux 2-Centre National de la Recherche Scientifique (CNRS), Institut de médecine moléculaire de Rangueil (I2MR), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-IFR150-Institut National de la Santé et de la Recherche Médicale (INSERM), Physiopathologie du cancer du foie, Université Bordeaux Segalen - Bordeaux 2-Institut National de la Santé et de la Recherche Médicale (INSERM), Oncogenesis Stress Signaling (OSS), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-CRLCC Eugène Marquis (CRLCC), Centre de Recherches en Cancérologie de Toulouse (CRCT), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Sciences et Technologies - Bordeaux 1 (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Toulouse (UT)-Université de Toulouse (UT)- Institut Fédératif de Recherche Bio-médicale Institution (IFR150)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Rennes (UR)-CRLCC Eugène Marquis (CRLCC), and Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)

Subjects
[SDV]Life Sciences [q-bio], Immunoblotting, perivascular growth, Kaplan-Meier Estimate, Protein Serine-Threonine Kinases, Mice, angiogenesis, Cell Movement, Cell Line, Tumor, Endoribonucleases, Pathology Section, Animals, Humans, Neoplasm Invasiveness, Cell Proliferation, Microscopy, Confocal, Neovascularization, Pathologic, Brain Neoplasms, glioblastoma, invasion, Xenograft Model Antitumor Assays, Tumor Burden, Doxycycline, Mutation, mesenchymal differentiation, Research Paper
Abstract

International audience; IRE1α is an endoplasmic reticulum (ER)-resident transmembrane signaling protein and a cellular stress sensor. The protein harbors a cytosolic dual kinase/endoribonuclease activity required for adaptive responses to micro-environmental changes. In an orthotopic xenograft model of human glioma, invalidation of IRE1α RNase or/and kinase activities generated tumors with remarkably distinct phenotypes. Contrasting with the extensive angiogenesis observed in tumors derived from control cells, the double kinase/RNase invalidation reprogrammed mesenchymal differentiation of cancer cells and produced avascular and infiltrative glioblastomas with blood vessel co-option. In comparison, selective invalidation of IRE1α RNase did not compromise tumor angiogenesis but still elicited invasive features and vessel co-option. In vitro, IRE1α RNase deficient cells were also endowed with a higher ability to migrate. Constitutive activation of both enzymes led to wild-type-like lesions. The presence of IRE1α, but not its RNase activity, is therefore required for glioblastoma neovascularization, whereas invasion results only from RNase inhibition. In this model, two key mechanisms of tumor progression and cancer cell survival are functionally linked to IRE1α

Published
2015

28. NGF-induced TrkA/CD44 association is involved in tumor aggressiveness and resistance to lestaurtinib

Author

Thierry Chassat, Robert-Alain Toillon, Matthieu Guilbert, François Bertucci, Cyril Corbet, Nicolas Magné, Eric Adriaenssens, Léo Aubert, Thomas Daubon, Elisabeth Génot, Xuefen Le Bourhis, Plasticité Cellulaire et Cancer - U908 (CPAC), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Signalisation des facteurs de croissance dans le cancer du sein. Protéomique fonctionnelle, Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Lille, Centre de recherche Cardio-Thoracique de Bordeaux [Bordeaux] (CRCTB), Université Bordeaux Segalen - Bordeaux 2-CHU Bordeaux [Bordeaux]-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de biologie de Lille - IBL (IBLI), Université de Lille, Sciences et Technologies-Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Université de Lille, Droit et Santé-Centre National de la Recherche Scientifique (CNRS), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP), Centre de Recherche en Cancérologie de Marseille (CRCM), Aix Marseille Université (AMU)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Laboratoire Angiogenèse et Micro-environnement des Cancers (LAMC), Université Sciences et Technologies - Bordeaux 1 (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de Cancérologie Lucien Neuwirth, Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne] (CHU ST-E), CHU Saint-Etienne, and Bertucci, François

Subjects
Proteomics, animal structures, Carbazoles, [SDV.CAN]Life Sciences [q-bio]/Cancer, Mice, SCID, Tropomyosin receptor kinase A, Biology, Mass Spectrometry, resistance, Mice, chemistry.chemical_compound, [SDV.CAN] Life Sciences [q-bio]/Cancer, Cell Line, Tumor, Nerve Growth Factor, medicine, Animals, Humans, Immunoprecipitation, Low-affinity nerve growth factor receptor, Biotinylation, Neoplasm Invasiveness, ROCK1, Gene Silencing, RNA, Small Interfering, Receptor, trkA, CD44, Kinase activity, Furans, ComputingMilieux_MISCELLANEOUS, NGF, TrkA, Lestaurtinib, Cell Membrane, lestaurtinib, Hyaluronan Receptors, Nerve growth factor, nervous system, Oncology, chemistry, Drug Resistance, Neoplasm, Cancer research, Female, K252a, Tyrosine kinase, Neoplasm Transplantation, Protein Binding, Signal Transduction, Research Paper, medicine.drug
Abstract

There is accumulating evidence that TrkA and its ligand Nerve Growth Factor (NGF) are involved in cancer development. Staurosporine derivatives such as K252a and lestaurtinib have been developed to block TrkA kinase signaling, but no clinical trial has fully demonstrated their therapeutic efficacy. Therapeutic failures are likely due to the existence of intrinsic signaling pathways in cancer cells that impede or bypass the effects of TrkA tyrosine kinase inhibitors. To verify this hypothesis, we combined different approaches including mass spectrometry proteomics, co-immunoprecipitation and proximity ligation assays. We found that NGF treatment induced CD44 binding to TrkA at the plasma membrane and subsequent activation of the p115RhoGEF/RhoA/ROCK1 pathway to stimulate breast cancer cell invasion. The NGF-induced CD44 signaling was independent of TrkA kinase activity. Moreover, both TrkA tyrosine kinase inhibition with lestaurtinib and CD44 silencing with siRNA inhibited cell growth in vitro as well as tumor development in mouse xenograft model; combined treatment significantly enhanced the antineoplastic effects of either treatment alone. Altogether, our results demonstrate that NGF-induced tyrosine kinase independent TrkA signaling through CD44 was sufficient to maintain tumor aggressiveness. Our findings provide an alternative mechanism of cancer resistance to lestaurtinib and indicate that dual inhibition of CD44 and TrkA tyrosine kinase activity may represent a novel therapeutic strategy.

Published
2015

29. The therapeutic response in Gorham's syndrome to the beta-blocking agent propranolol is correlated to VEGF-A, but not to VEGF-C or FLT1 expression

Author

Baud, Jessica, Lomri, Abderrahim, Graber, Denis, Bikfalvi, Andreas, Laboratoire Angiogenèse et Micro-environnement des Cancers (LAMC), Université Sciences et Technologies - Bordeaux 1 (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Bordeaux (UB), Service de pédiatrie [Hôpital Saint-Louis, La Rochelle], This work was supported by funding from the « Institut National de la Santé et de la Recherche médicale (INSERM) »., and Bodescot, Myriam

Subjects
[SDV.MHEP.HEM] Life Sciences [q-bio]/Human health and pathology/Hematology, Medicine(all), Vascular Endothelial Growth Factor A, Vascular Endothelial Growth Factor Receptor-1, Adolescent, Neovascularization, Pathologic, Biochemistry, Genetics and Molecular Biology(all), Gorham’s syndrome, Adrenergic beta-Antagonists, Vascular Endothelial Growth Factor C, [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology, Case Report, Propranolol, VEGF, Treatment Outcome, Humans, Female, Osteolysis, Essential, Angiogenesis, Lymphangiogenesis
Abstract

Background Gorham’s syndrome is a rare illness of unknown etiology. It is characterized by a local proliferation of blood or lymphatic vessels that in bones leads to progressive resorption and destruction. The cause of the disease is not elucidated, and therapeutic options remain limited. Case presentation We report herein the case of a young female Caucasian patient aged 18 years with diffuse Gorham syndrome. In tissue specimens angiogenesis and massive lymphangiogenesis as well as the expression of vascular endothelial growth factor-A (VEGF-A) and neuropilins was observed. Lymphangiogenesis is a prominent feature of the disease and a number of lymphatic markers were found to be expressed, however only VEGF-A, but not vascular endothelial growth factor-C (VEGF-C) was found to be elevated in the circulation. Circulating levels of soluble VEGF receptor-1 were also not elevated. Furthermore, the patient responded favorably and the disease was stabilized following treatment with the beta-blocking agent Propranolol alone which acts on VEGF-A alone, but not on soluble VEGF receptor-1 levels. Conclusion This suggests that the disease is dependent on VEGF-A, but on neither VEGF-C, the major driver of lymphangiogenesis, nor FLT1. Furthermore, Propranolol acts on VEGF-A but not FLT1 expression. Electronic supplementary material The online version of this article (doi:10.1186/s13104-015-1259-9) contains supplementary material, which is available to authorized users.

Published
2014

30. Computational Modelling of Metastasis Development in Renal Cell Carcinoma

Author

Olivier Saut, Etienne Baratchart, Wilfried Souleyreau, Emeline J. Ribot, Lindsay S. Cooley, Sebastien Benzekry, Andreas Bikfalvi, Raphael Pineau, Thierry Colin, Modélisation Mathématique pour l'Oncologie (MONC), Institut de Mathématiques de Bordeaux (IMB), Université Bordeaux Segalen - Bordeaux 2-Université Sciences et Technologies - Bordeaux 1-Université de Bordeaux (UB)-Institut Polytechnique de Bordeaux (Bordeaux INP)-Centre National de la Recherche Scientifique (CNRS)-Université Bordeaux Segalen - Bordeaux 2-Université Sciences et Technologies - Bordeaux 1-Université de Bordeaux (UB)-Institut Polytechnique de Bordeaux (Bordeaux INP)-Centre National de la Recherche Scientifique (CNRS)-Institut Bergonié [Bordeaux], UNICANCER-UNICANCER-Inria Bordeaux - Sud-Ouest, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria), Laboratoire Angiogenèse et Micro-environnement des Cancers (LAMC), Université Sciences et Technologies - Bordeaux 1-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Bordeaux (UB), Centre de résonance magnétique des systèmes biologiques (CRMSB), Centre National de la Recherche Scientifique (CNRS)-Université de Bordeaux (UB), The authors would like to thank the PlanCancer from the National Cancer Institute (INCA) and the National Institute of Health and Medical Research (INSERM) for financial support of this project (MetaSys grant to A.B and T.C). L.C,(Post-doctoral fellowship) and E.B. (PhD Fellowship) were supported by the MetaSys Grant. This work is part of the PhD thesis project of E.B. This study has been carried out within the frame of the LABEX TRAIL, ANR-10-LABX-0057 with financial support from the French State, managed by the French National Research Agency (ANR) in the frame of the 'Investments for the future' Programme IdEx (ANR-10-IDEX-03-02)., MetaSys and MIMOSA, Université Bordeaux Segalen - Bordeaux 2-Université Sciences et Technologies - Bordeaux 1 (UB)-Université de Bordeaux (UB)-Institut Polytechnique de Bordeaux (Bordeaux INP)-Centre National de la Recherche Scientifique (CNRS)-Université Bordeaux Segalen - Bordeaux 2-Université Sciences et Technologies - Bordeaux 1 (UB)-Université de Bordeaux (UB)-Institut Polytechnique de Bordeaux (Bordeaux INP)-Centre National de la Recherche Scientifique (CNRS)-Institut Bergonié [Bordeaux], Université Sciences et Technologies - Bordeaux 1 (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS), and Baratchart, Etienne

Subjects
Multiple tumours, Metastatic lesions, QH301-705.5, [SDV.CAN]Life Sciences [q-bio]/Cancer, Biology, Models, Biological, Metastatic tumours, Metastasis, Mice, Cellular and Molecular Neuroscience, Breast cancer, [SDV.CAN] Life Sciences [q-bio]/Cancer, Renal cell carcinoma, Genetics, medicine, Carcinoma, Animals, metastasis, Computer Simulation, Neoplasm Metastasis, Biology (General), Carcinoma, Renal Cell, Molecular Biology, Ecology, Evolution, Behavior and Systematics, cancer modelling, [SDV.BIBS] Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], Ecology, medicine.diagnostic_test, Computational Biology, Magnetic resonance imaging, medicine.disease, [SDV.BIBS]Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], Kidney Neoplasms, 3. Good health, Computational Theory and Mathematics, Modeling and Simulation, Immunology, Cancer research, Female, Research Article
Abstract

The biology of the metastatic colonization process remains a poorly understood phenomenon. To improve our knowledge of its dynamics, we conducted a modelling study based on multi-modal data from an orthotopic murine experimental system of metastatic renal cell carcinoma. The standard theory of metastatic colonization usually assumes that secondary tumours, once established at a distant site, grow independently from each other and from the primary tumour. Using a mathematical model that translates this assumption into equations, we challenged this theory against our data that included: 1) dynamics of primary tumour cells in the kidney and metastatic cells in the lungs, retrieved by green fluorescent protein tracking, and 2) magnetic resonance images (MRI) informing on the number and size of macroscopic lesions. Critically, when calibrated on the growth of the primary tumour and total metastatic burden, the predicted theoretical size distributions were not in agreement with the MRI observations. Moreover, tumour expansion only based on proliferation was not able to explain the volume increase of the metastatic lesions. These findings strongly suggested rejection of the standard theory, demonstrating that the time development of the size distribution of metastases could not be explained by independent growth of metastatic foci. This led us to investigate the effect of spatial interactions between merging metastatic tumours on the dynamics of the global metastatic burden. We derived a mathematical model of spatial tumour growth, confronted it with experimental data of single metastatic tumour growth, and used it to provide insights on the dynamics of multiple tumours growing in close vicinity. Together, our results have implications for theories of the metastatic process and suggest that global dynamics of metastasis development is dependent on spatial interactions between metastatic lesions., Author Summary We used mathematical modelling to formalize the standard theory of metastatic initiation, under which secondary tumours, after establishment in a distant organ, grow independently from each other and from the primary tumour. When calibrated on the experimental data of primary tumour and total metastatic burden in the lungs in an animal model of renal cell carcinoma, the initial model predicted a size distribution of metastatic foci that did not fit with observations obtained experimentally using magnetic resonance imaging (which provided size and number of macro-metastases). The model predicted an increase in the number of lesions, but of smaller size when compared to the data. This led us to revise the standard theory and to propose two hypotheses in order to explain the observations: 1) small metastatic foci merge into larger ones and/or 2) circulating tumour cells may join already established tumours. We then derived a spatial model of tumour growth in order to explore the quantitative implications of tumours merging on global tumour growth and estimated the numbers of required metastatic foci to obtain the observed metastatic volumes.

Published
2015

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