Author: "Julie Gavard" / Topic: cancer research - Searchworks@Jio Institute Digital Library Search Results

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1. Abstract P3-11-09: Extracellular vesicle-based biomarker assay for the monitoring of the efficacy of frontline endocrine therapy + CDK4-6 inhibitors in metastatic breast cancer

Author: Mathilde Richard, Jean Sebastien FRENEL, Laurent Mathiot, Mario Campone, Mathilde Colombie, Marie Robert, Anne Patsouris, Frederic Bigot, Julie Gavard, Gwennan André-Grégoire, and Laetitia Guevel
Subjects: Cancer Research, Oncology
Abstract: CONTEXT: Endocrine therapy combined with CDK4/6 inhibitor is the standard frontline treatment for the vast majority of HR+/HER2- metastatic breast cancer (MBC) patients. Despite an overall survival benefit, patients eventually progress and mechanisms of resistance to this combination are not well identified. Non-invasive monitoring of the efficacy of treatment could help into tailoring therapeutic regimen. Extracellular vesicles (EVs) are a group of heterogeneous nanosized bioparticles (30-1000nm), released by almost all cell types - including tumor, platelets, and immune cells – carrying informative biological material emanating from the mother cell and circulating in the blood stream. In this project, we ambition to assess whether the vesiclemia, i.e. plasmatic extracellular vesicle concentration can be used as a clinic-biological parameter to assist in the monitoring of patients. METHODS: EPICURE is an ongoing pilot prospective cohort study of heterogeneous and massive data integration, i.e. multi-omics approaches in MBC patients. The present study focused on patients with HR+/HER2- MBC receiving frontline endocrine therapy+iCDK4/6. Plasma samples were drawn every 3 months during the treatment until progression. The workflow for the enrichment of circulating EVs was developed from frozen plasma. A semi-automatized isolation procedure using size exclusion chromatography combined with the newly developed interference light microscopy apparatus Videodrop allowed to routinely separate plasmatic EVs and quantify vesiclemia in a fast and reliable manner for a large number of samples (longitudinal follow-up of MBC patients). RESULTS: 26 patients were included and monitored for vesiclemia. Median age was 58.5y (±13.7). Metastatic disease sites were distributed as follows: bone metastases (21; 84%), liver (21; 84%), thoracic (10; 40%), node (2; 8%), brain (1; 4%), others (2; 8%). Endocrine therapy included aromatase inhibitors (20; 77%), fulvestrant (6; 29%), GnRH agonists (5; 19%) and CDK4/6 inhibitors palbocilib (15; 57%), abemaciclib (8; 31%) and ribociclib (3; 11%). With a median follow-up time of 22.1 months (95%CI 21.2 - not reached), median progression free survival was 21.8 months (95%CI 18.1 - not reached). Median time on treatment was 19.4 months (IQR 11.6 - 22.1). Objective response rate was confirmed in 12 patients (6 with complete response). Out of the 26 patients, 12 stopped the frontline treatment due to disease progression. 135 longitudinal follow-up samples were analyzed for EVs. All patients who progressed rapidly after treatment initiation (i.e median PFS< 6 months) had an increased vesiclemia at the months 2 and 6 after inclusion. Conversely, patients who had a median PFS >18m had a stable vesiclemia during this period. CONCLUSION This study aims to use circulating EVs as a therapeutic companion to anticipate treatment resistance and tumor progression in MBC patients. Our preliminary data suggest that the vesiclemia could be used as a predictive tool to anticipate treatment failure, and thus might be used to tailor treatments in time. Citation Format: Mathilde Richard, Jean Sebastien FRENEL, Laurent Mathiot, Mario Campone, Mathilde Colombie, Marie Robert, Anne Patsouris, Frederic Bigot, Julie Gavard, Gwennan André-Grégoire, Laetitia Guevel. Extracellular vesicle-based biomarker assay for the monitoring of the efficacy of frontline endocrine therapy + CDK4-6 inhibitors in metastatic breast cancer. [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P3-11-09.
Published: 2023
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2. Challenges in glioblastoma research: focus on the tumor microenvironment

Author: Andreas Bikfalvi, Cristine Alves da Costa, Tony Avril, Jean-Vianney Barnier, Luc Bauchet, Lucie Brisson, Pierre Francois Cartron, Hélène Castel, Eric Chevet, Hervé Chneiweiss, Anne Clavreul, Bruno Constantin, Valérie Coronas, Thomas Daubon, Monique Dontenwill, Francois Ducray, Natacha Entz-Werlé, Dominique Figarella-Branger, Isabelle Fournier, Jean-Sébastien Frenel, Mathieu Gabut, Thierry Galli, Julie Gavard, Gilles Huberfeld, Jean-Philippe Hugnot, Ahmed Idbaih, Marie-Pierre Junier, Thomas Mathivet, Philippe Menei, David Meyronet, Céline Mirjolet, Fabrice Morin, Jean Mosser, Elisabeth Cohen-Jonathan Moyal, Véronique Rousseau, Michel Salzet, Marc Sanson, Giorgio Seano, Emeline Tabouret, Aurélie Tchoghandjian, Laurent Turchi, Francois M. Vallette, Somya Vats, Maité Verreault, Thierry Virolle, BoRdeaux Institute in onCology (Inserm U1312 - BRIC), Université de Bordeaux (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de pharmacologie moléculaire et cellulaire (IPMC), 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)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), Oncogenesis, Stress, Signaling (OSS), Université de Rennes (UR)-CRLCC Eugène Marquis (CRLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM), CRLCC Eugène Marquis (CRLCC), Institut des Neurosciences Paris-Saclay (NeuroPSI), Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Institut de Génomique Fonctionnelle (IGF), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), Centre de Recherche en Cancérologie et Immunologie Intégrée Nantes-Angers (CRCI2NA ), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Nantes Université - UFR de Médecine et des Techniques Médicales (Nantes Univ - UFR MEDECINE), Nantes Université - pôle Santé, Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ)-Nantes Université - pôle Santé, Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ), Différenciation et communication neuronale et neuroendocrine (DC2N), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institute for Research and Innovation in Biomedicine (IRIB), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Neuroscience Paris Seine (NPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), Canaux et Connexines dans les Cancers et Cellules Souches (4CS), Université de Poitiers-Centre National de la Recherche Scientifique (CNRS), Institut de biochimie et génétique cellulaires (IBGC), Université Bordeaux Segalen - Bordeaux 2-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Bioimagerie et Pathologies (LBP), Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS), Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [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), Centre Léon Bérard [Lyon], Service d'Anatomie Pathologique et de Neuropathologie [Hôpital de la Timone - CHU - APHM], Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), Protéomique, Réponse Inflammatoire, Spectrométrie de Masse (PRISM) - U 1192 (PRISM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), CHU Lille, Institut de psychiatrie et neurosciences de Paris (IPNP - U1266 Inserm), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), GHU Paris Psychiatrie et Neurosciences, Centre interdisciplinaire de recherche en biologie (CIRB), Labex MemoLife, École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Collège de France (CdF (institution))-Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut du Cerveau = Paris Brain Institute (ICM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Hospices Civils de Lyon, Departement de Neurologie (HCL), Equipe CADIR (LNC - U1231), Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Agro Dijon, Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Agro Dijon, Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro), Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), UNICANCER, Centre de Recherches en Cancérologie de Toulouse (CRCT), 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)-Centre National de la Recherche Scientifique (CNRS), Institut Claudius Regaud, CHU Charles Foix [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Signalisation, radiobiologie et cancer, Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Institut de neurophysiopathologie (INP), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Institut de Biologie Valrose (IBV), 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), ARC research grant ‘Fondation ARC’ 2018-2019 Role of PRL phosphatases in angiogenesis, Labellisation ARC ‘GliomaGuide’ (2018-2020), INCa PLBIO21-24, Ligue Contre le Cancer, Plan Cancer, Fondation ARC, ARTC, Cancéropôle Grand Sud Ouest to T.D., la Ligue Contre le Cancer (Comité Charente Maritime) to B.C. and VC, ARTC-sud to E.T., EU Transcan ERA Net Consortium grant ‘GliomaPRD’ (2018-2021), INCa PLBIO20-23 to T.D., E.C, Conseil Regional d’Aquitaine (2018-20019), Ligue Contre le Cancer (2017-2021) to A.B, INCa PLBIO17-220 to M.G, INCa PLBIO17-20 to E.C., Cancéropôle Grand-Ouest to E.C., F.V., J.G., and L.B., French Preclinical Brain Tumor Study Group ‘GrOupe Préclinique de l’Anocef’ (GOPA), figarella-branger, dominique, 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], Cancer Research, Oncology, Invasion, Tumor microenvironnement, [SDV]Life Sciences [q-bio], Resistance to therapy, Glioblastoma
Abstract: International audience; Glioblastoma (GBM) is the most deadly type of malignant brain tumor, despite extensive molecular analyses of GBM cells. In recent years, the tumor microenvironment (TME) has been recognized as an important player and therapeutic target in GBM. However, there is a need for a full and integrated understanding of the different cellular and molecular components involved in the GBM TME and their interactions for the development of more efficient therapies. In this review, we provide a comprehensive report of the GBM TME, which assembles the contributions of physicians and translational researchers working on brain tumor pathology and therapy in France. We propose a holistic view of the subject by delineating the specific features of the GBM TME at the cellular, molecular, and therapeutic levels.
Published: 2023
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3. Antiangiogenic Compound Axitinib Demonstrates Low Toxicity and Antitumoral Effects against Medulloblastoma

Author: Marina Pagnuzzi-Boncompagni, Vincent Picco, Valérie Vial, Victor Planas-Bielsa, Ashaina Vandenberghe, Thomas Daubon, Marie-Alix Derieppe, Christopher Montemagno, Jérôme Durivault, Renaud Grépin, Sonia Martial, Jérôme Doyen, Julie Gavard, Gilles Pagès, Centre Scientifique de Monaco (CSM), Institut de biochimie et génétique cellulaires (IBGC), Université Bordeaux Segalen - Bordeaux 2-Centre National de la Recherche Scientifique (CNRS), Université de Bordeaux (UB), 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), Université Côte d'Azur (UCA), Signaling in Oncogenesis, Angiogenesis and Permeability - SOAP (CRCI2NA / Eq 6), Centre de Recherche en Cancérologie et Immunologie Intégrée Nantes-Angers (CRCI2NA ), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Nantes Université - UFR de Médecine et des Techniques Médicales (Nantes Univ - UFR MEDECINE), Nantes Université - pôle Santé, Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ)-Nantes Université - pôle Santé, Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Nantes Université - UFR de Médecine et des Techniques Médicales (Nantes Univ - UFR MEDECINE), Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ), and Bernardo, Elizabeth
Subjects: Cancer Research, angiogenesis, pediatric brain cancer, medulloblastoma, targeted therapy, [SDV.CAN] Life Sciences [q-bio]/Cancer, Oncology, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, [SDV.CAN]Life Sciences [q-bio]/Cancer, RC254-282, Article
Abstract: Simple Summary Medulloblastoma is the most frequent pediatric brain cancer. Despite great improvements in the treatment of this disease over the last decades, survivors are subject to debilitating adverse effects that strongly impair their quality of life. There is an urgent need to find efficient anticancer therapies with fewer toxic effects. In this study, we suggest that an FDA- and EMA-approved antiangiogenic compound named axitinib may display effective antitumoral effects and low toxicity towards children as compared to a reference treatment currently used in clinical protocols. We also show that this compound can enter the brain compartment and exert antitumoral effects in vivo. Our study paves the way towards a clinical trial of repurposing axitinib to a pediatric brain cancer indication. Abstract Background: Despite the improvement of medulloblastoma (MB) treatments, survivors face severe long-term adverse effects and associated morbidity following multimodal treatments. Moreover, relapses are fatal within a few months. Therefore, chemotherapies inducing fewer adverse effects and/or improving survival at relapse are key for MB patients. Our purpose was to evaluate the last-generation antiangiogenic drugs for their relevance in the therapeutic arsenal of MB. Methods: We screened three EMA- and FDA-approved antiangiogenic compounds (axitinib, cabozantinib and sunitinib) for their ability to reduce cell viability of five MB cell lines and their low toxicity towards two normal cell lines in vitro. Based on this screening, single-agent and combination therapies were designed for in vivo validation. Results: Axitinib, cabozantinib and sunitinib decreased viability of all the tested tumor cells. Although sunitinib was the most efficient in tumor cells, it also impacted normal cells. Therefore, axitinib showed the highest selectivity index for MB cells as compared to normal cells. The compound did not lead to acute toxicity in juvenile rats and crossed the blood–brain barrier. Moreover, axitinib efficiently reduced the growth rate of experimental brain tumors. Analysis of public databases showed that high expression of axitinib targets correlates with poor prognosis. Conclusion: Our results suggest that axitinib is a compelling candidate for MB treatment.
Published: 2021
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4. The von Willebrand Factor stamps Plasmatic Extracellular Vesicles from Glioblastoma Patients

Author: Emmanuel Jouglar, Gwennan André-Grégoire, Quentin Sabbagh, Jean-Sebastien Frenel, Nicolas Bidère, Carolina Alves-Nicolau, Aurélien Dupont, Laetitia Guevel, Julie Gavard, Signaling in Oncogenesis, Angiogenesis and Permeability (CRCINA-ÉQUIPE 15), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), Institut de Cancérologie de l'Ouest [Angers/Nantes] (UNICANCER/ICO), UNICANCER, Biosit : biologie, santé, innovation technologique (SFR UMS CNRS 3480 - INSERM 018), Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Signaling in Oncogenesis, Angiogenesis and Permeability - SOAP (CRCI2NA / Eq 6), Centre de Recherche en Cancérologie et Immunologie Intégrée Nantes-Angers (CRCI2NA ), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Nantes Université - UFR de Médecine et des Techniques Médicales (Nantes Univ - UFR MEDECINE), Nantes Université - pôle Santé, Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ)-Nantes Université - pôle Santé, Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Nantes Université - UFR de Médecine et des Techniques Médicales (Nantes Univ - UFR MEDECINE), Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Gavard, Julie, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), and Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)
Subjects: Male, Cell biology, Proteome, Science, [SDV]Life Sciences [q-bio], Tumor burden, Extracellular vesicles, Article, Extracellular Vesicles, 03 medical and health sciences, 0302 clinical medicine, Individual health, Von Willebrand factor, von Willebrand Factor, Biomarkers, Tumor, Tumor Microenvironment, Humans, Medicine, Aged, Cancer, 030304 developmental biology, Aged, 80 and over, 0303 health sciences, Tumor microenvironment, Multidisciplinary, biology, Brain Neoplasms, business.industry, Extracellular vesicle, Middle Aged, Prognosis, medicine.disease, [SDV] Life Sciences [q-bio], Case-Control Studies, 030220 oncology & carcinogenesis, biology.protein, Cancer research, Female, Glioblastoma, business, Homeostasis, Follow-Up Studies
Abstract: Glioblastoma is a devastating tumor of the central nervous system characterized by a poor survival and an extremely dark prognosis, making its diagnosis, treatment and monitoring highly challenging. Numerous studies have highlighted extracellular vesicles (EVs) as key players of tumor growth, invasiveness and resistance, as they carry and disseminate oncogenic material in the local tumor microenvironment and at distance. However, whether their quality and quantity reflect individual health status and changes in homeostasis is still not fully elucidated. Here, we separated EVs from plasma collected at different time points alongside with the clinical management of GBM patients. Our findings confirm that plasmatic EVs could be separated and characterized with standardized protocols, thereby ensuring the reliability of measuring vesiclemia, i.e. extracellular vesicle concentration in plasma. This unveils that vesiclemia is a dynamic parameter, which could be reflecting tumor burden and/or response to treatments. Further label-free liquid chromatography tandem mass spectrometry unmasks the von Willebrand Factor (VWF) as a selective protein hallmark for GBM-patient EVs. Our data thus support the notion that EVs from GBM patients showed differential protein cargos that can be further surveyed in circulating EVs, together with vesiclemia.
Published: 2021
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5. Deciphering Tumor Niches: Lessons From Solid and Hematological Malignancies

Author: Stéphane J.C. Mancini, Karl Balabanian, Isabelle Corre, Julie Gavard, Gwendal Lazennec, Marie-Caroline Le Bousse-Kerdilès, Fawzia Louache, Véronique Maguer-Satta, Nathalie M. Mazure, Fatima Mechta-Grigoriou, Jean-François Peyron, Valérie Trichet, Olivier Herault, Microenvironnement des niches tumorales [UNIV Tours] (CNRS GDR 3697 MicroNiT), Université de Tours-Centre National de la Recherche Scientifique (CNRS), Etablissement Français du Sang Bretagne, EFS, Cancéropôle Grand-Ouest [Bretagne-Centre-Pays de Loire], Microenvironment, Cell Differentiation, Immunology and Cancer (MICMAC), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Ecotaxie, microenvironnement et développement lymphocytaire (EMily (UMR_S_1160 / U1160)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Institut Carnot, Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA), Centre Intégré d'Oncologie Nantes/Angers, Sys2Diag-Modélisation et Ingénierie des Systèmes Complexes Biologiques pour le Diagnostic (Sys2Diag), Centre National de la Recherche Scientifique (CNRS)-Alcediag, Interactions cellules souches-niches : physiologie, tumeurs et réparation tissulaire, Service de Santé des Armées-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre méditerranéen de médecine moléculaire (C3M), 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)-Institut National de la Santé et de la Recherche Médicale (INSERM), Unité de génétique et biologie des cancers (U830), Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Sarcomes osseux et remodelage des tissus calcifiés - Phy-Os [Nantes - INSERM U1238] (Phy-Os), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Bretagne Loire (UBL)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), ERL 7001 LNOx (Leukemic Niche & redOx metabolism / Niche leucémique et métabolisme redOx) (LNOx), Groupe innovation et ciblage cellulaire (GICC), EA 7501 [2018-...] (GICC EA 7501), Université de Tours-Université de Tours-Centre National de la Recherche Scientifique (CNRS)-Centre Hospitalier Régional Universitaire de Tours (CHRU TOURS), CHU Trousseau [Tours], Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Université de Tours (UT)-Centre National de la Recherche Scientifique (CNRS), Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université Bretagne Loire (UBL), Université de Tours (UT)-Université de Tours (UT)-Centre National de la Recherche Scientifique (CNRS)-Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), CNRS GDR 3697 MicroNiT, Centre National de la Recherche Scientifique (CNRS), CNRS UMR9005, Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), Signaling in Oncogenesis, Angiogenesis and Permeability - SOAP (CRCI2NA / Eq 6), Centre de Recherche en Cancérologie et Immunologie Intégrée Nantes-Angers (CRCI2NA ), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Nantes Université - UFR de Médecine et des Techniques Médicales (Nantes Univ - UFR MEDECINE), Nantes Université - pôle Santé, Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ)-Nantes Université - pôle Santé, Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Nantes Université - UFR de Médecine et des Techniques Médicales (Nantes Univ - UFR MEDECINE), Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), 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)-Université Côte d'Azur (UCA), Université de Tours (UT), Lazennec, Gwendal, Signaling in Oncogenesis, Angiogenesis and Permeability (CRCINA-ÉQUIPE 15), Centre hospitalier universitaire de Nantes (CHU Nantes)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Nantes (UN)-Université d'Angers (UA)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Nantes (UN)-Université d'Angers (UA), Centre hospitalier universitaire de Nantes (CHU Nantes)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Nantes (UN)-Université d'Angers (UA), Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)-Centre National de la Recherche Scientifique (CNRS)-Groupe innovation et ciblage cellulaire (GICC), EA 7501 [2018-...] (GICC EA 7501), and Université de Tours (UT)-Université de Tours (UT)
Subjects: Stromal cell, endothelial plasticity, Angiogenesis, Mini Review, [SDV]Life Sciences [q-bio], Niche, Immunology, Context (language use), [SDV.CAN]Life Sciences [q-bio]/Cancer, Cell Communication, cytokines and chemokines, Biology, cancer-associated fibroblasts (CAFs), 03 medical and health sciences, angiogenesis, 0302 clinical medicine, [SDV.CAN] Life Sciences [q-bio]/Cancer, Cancer-Associated Fibroblasts, Cancer stem cell, Neoplasms, medicine, Tumor Microenvironment, Immunology and Allergy, Animals, Humans, 030304 developmental biology, 0303 health sciences, Neovascularization, Pathologic, energy/oxidative metabolism, Mesenchymal stem cell, mitochondrial transfer, Mesenchymal Stem Cells, RC581-607, microenvironment, 3. Good health, Haematopoiesis, medicine.anatomical_structure, mesenchymal stem/stromal cells (MSCs), 030220 oncology & carcinogenesis, Cancer research, Cytokines, Bone marrow, Endothelium, Vascular, Immunologic diseases. Allergy
Abstract: International audience; Knowledge about the hematopoietic niche has evolved considerably in recent years, in particular through in vitro analyzes, mouse models and the use of xenografts. Its complexity in the human bone marrow, in particular in a context of hematological malignancy, is more difficult to decipher by these strategies and could benefit from the knowledge acquired on the niches of solid tumors. Indeed, some common features can be suspected, since the bone marrow is a frequent site of solid tumor metastases. Recent research on solid tumors has provided very interesting information on the interactions between tumoral cells and their microenvironment, composed notably of mesenchymal, endothelial and immune cells. This review thus focuses on recent discoveries on tumor niches that could help in understanding hematopoietic niches, with special attention to 4 particular points: i) the heterogeneity of carcinoma/cancer-associated fibroblasts (CAFs) and mesenchymal stem/stromal cells (MSCs), ii) niche cytokines and chemokines, iii) the energy/oxidative metabolism and communication, especially mitochondrial transfer, and iv) the vascular niche through angiogenesis and endothelial plasticity. The elements highlighted in this review identify actors and/or pathways of the microenvironment that are broadly and often involved in cancer processes. This would open avenues for innovative therapeutic opportunities targeting not only cancer stem cells but also their regulatory tumor niche(s), in order to improve current antitumor therapies.
Published: 2021
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6. Loss of the Metastasis Suppressor NME1, But Not of Its Highly Related Isoform NME2, Induces a Hybrid Epithelial–Mesenchymal State in Cancer Cells

Author: David Bernard, Sylvie Coscoy, Teresita Padilla-Benavides, Anda Huna, Julie Gavard, B. Nawrocki-Raby, Mathieu Boissan, Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [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), Pathologies Pulmonaires et Plasticité Cellulaire - UMR-S 1250 (P3CELL), Université de Reims Champagne-Ardenne (URCA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Wesleyan University, Signaling in Oncogenesis, Angiogenesis and Permeability (CRCINA-ÉQUIPE 15), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA), Département d'Oncologie [Saint Herblain], Institut de Cancérologie de l'Ouest [Angers/Nantes] (UNICANCER/ICO), UNICANCER-UNICANCER, Laboratoire Physico-Chimie Curie [Institut Curie] (PCC), Institut Curie [Paris]-Institut de Chimie du CNRS (INC)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Equipe labellisée Ligue contre le Cancer, Centre de Recherche Saint-Antoine (CR Saint-Antoine), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service de biochimie et hormonologie [CHU Tenon], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Tenon [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), Centre de Recherche Saint-Antoine (CRSA), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), and Bernardo, Elizabeth
Subjects: Epithelial-Mesenchymal Transition, MAP Kinase Signaling System, Cell, Mice, Nude, Triple Negative Breast Neoplasms, [SDV.CAN]Life Sciences [q-bio]/Cancer, epithelial–mesenchymal transition, Catalysis, Article, Metastasis, lcsh:Chemistry, Inorganic Chemistry, 03 medical and health sciences, 0302 clinical medicine, [SDV.CAN] Life Sciences [q-bio]/Cancer, Cell Line, Tumor, medicine, Cell Adhesion, Animals, Humans, cancer, metastasis, Metastasis suppressor, Epithelial–mesenchymal transition, Physical and Theoretical Chemistry, lcsh:QH301-705.5, Molecular Biology, Protein kinase B, Spectroscopy, 030304 developmental biology, Gene Editing, 0303 health sciences, Chemistry, Organic Chemistry, Mesenchymal stem cell, Cancer, General Medicine, NM23 Nucleoside Diphosphate Kinases, medicine.disease, Cadherins, Computer Science Applications, medicine.anatomical_structure, lcsh:Biology (General), lcsh:QD1-999, 030220 oncology & carcinogenesis, Cancer cell, Cancer research, Female, epithelium
Abstract: International audience; Epithelial–mesenchymal transition (EMT) is important for the initial steps of metastasis. Although it is well accepted that the nucleoside diphosphate kinase NME1 is a metastasis suppressor, its effect on EMT remains poorly documented, as does that of its closely related isoform, NME2. Here, by using gene silencing, inactivation and overexpression strategies in a variety of cellular models of cancer, we show that NME1 is a powerful inhibitor of EMT. Genetic manipulation of NME2, by contrast, had no effect on the EMT phenotype of cancer cells, indicating a specific function of NME1 in EMT regulation. Loss of NME1 in epithelial cancer cells resulted in a hybrid phenotype intermediate between epithelial and mesenchymal cells, which is known to be associated with cells with a highly metastatic character. Conversely, overexpression of NME1 in mesenchymal cancer cells resulted in a more epithelial phenotype. We found that NME1 expression was negatively associated with EMT markers in many human cancers and was reduced in human breast tumor cell lines with the aggressive ‘triple-negative’ phenotype when compared to human breast tumor cell lines positive for estrogen receptor. We show that NME1, but not NME2, is an inhibitor of essential concerted intracellular signaling pathways involved in inducing EMT, including the AKT and MAPK (ERK, p38, and JNK) pathways. Additionally, NME1 depletion considerably altered the distribution of E-cadherin, a gatekeeper of the epithelial phenotype, shifting it from the plasma membrane to the cytosol and resulting in less E-cadherin on the cell surface than in control cells. Functional aggregation and dispersion assays demonstrated that inactivation of NME1 decreases E-cadherin-mediated cell–cell adhesion. We conclude that NME1, but not NME2, acts specifically to inhibit EMT and prevent the earliest stages of metastasis.
Published: 2021
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7. The von Willebrand Factor stamps Plasmatic Extracellular Vesicles from Glioblastoma Patients

Author: Laetitia Guevel, Julie Gavard, Emmanuel Jouglar, Gwennan André-Grégoire, Nicolas Bidère, Jean-Sébastien Frenel, Carolina Alves-Nicolau, and Quentin Sabbagh
Subjects: Tumor microenvironment, biology, business.industry, Tumor burden, Extracellular vesicle, medicine.disease, Extracellular vesicles, Von Willebrand factor, biology.protein, Cancer research, Medicine, Tumor growth, business, Homeostasis, Glioblastoma
Abstract: Glioblastoma is a devastating tumor of the central nervous system characterized by a poor survival and an extremely dark prognosis, making its diagnosis, treatment and monitoring highly challenging. Numerous studies have highlighted extracellular vesicles (EVs) as key players of tumor growth, invasiveness and resistance, as they carry and disseminate oncogenic material in the local tumor microenvironment and at distance. However, whether their quality and quantity reflect individual health status and changes in homeostasis is still not fully elucidated. Here, we separated EVs from plasma collected at different time points alongside with the clinical management of GBM patients. Our findings confirm that plasmatic EVs could be separated and characterized with standardized protocols, thereby ensuring the reliability of measuring vesiclemia, i.e. extracellular vesicle concentration in plasma. This unveils that vesiclemia is a dynamic parameter, which could be reflecting tumor burden and/or response to treatments. Further label-free liquid chromatography tandem mass spectrometry unmasks the von Willebrand Factor (VWF) as a selective protein hallmark for GBM-patient EVs. Our data thus support the notion that EVs from GBM patients showed differential protein cargos that can be further surveyed in circulating EVs, together with vesiclemia.
Published: 2021
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8. Author response: Ral GTPases promote breast cancer metastasis by controlling biogenesis and organ targeting of exosomes

Author: Coralie Spiegelhalter, Frédéric Gros, Anne-Marie Haeberlé, Ignacio Busnelli, Christine Carapito, Vincent Mittelheisser, Nicolas Vitale, Jacky G. Goetz, Marcel Blot-Chabaud, Julie Gavard, Laetitia Fouillen, Paul Timpson, Nandini Asokan, Gwennan André-Grégoire, Alexandre Detappe, Raphael Carapito, Benjamin Mary, Olivier Lefebvre, Naël Osmani, Shima Ghoroghi, Kendelle J. Murphy, Nicodème Paul, Annabel Larnicol, Vincent Hyenne, Annick Klein, Catherine A. Royer, Sébastien Halary, and François Delalande
Subjects: business.industry, Cancer research, Medicine, Breast cancer metastasis, GTPase, business, Microvesicles, Biogenesis
Published: 2020
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9. Vesiclemia: counting on extracellular vesicles for glioblastoma patients

Author: Laetitia Guevel, Quentin Sabbagh, Julie Gavard, Gwennan André-Grégoire, Signaling in Oncogenesis, Angiogenesis and Permeability (CRCINA-ÉQUIPE 15), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), SIRIC ILIAD [Angers, Nantes], Institut de Cancérologie de l'Ouest [Angers/Nantes] (UNICANCER/ICO), UNICANCER, Bernardo, Elizabeth, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), and Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)
Subjects: 0301 basic medicine, Cancer Research, [SDV.CAN]Life Sciences [q-bio]/Cancer, Cell Communication, Biology, Cell Fractionation, Extracellular vesicles, 03 medical and health sciences, Paracrine signalling, Extracellular Vesicles, 0302 clinical medicine, [SDV.CAN] Life Sciences [q-bio]/Cancer, Genetics, medicine, Biomarkers, Tumor, Tumor Microenvironment, Animals, Humans, Tumor growth, Molecular Biology, Noninvasive biomarkers, Brain Neoplasms, Disease Management, Biological Transport, medicine.disease, 3. Good health, 030104 developmental biology, Molecular Diagnostic Techniques, 030220 oncology & carcinogenesis, Cancer research, Disease Progression, Glioblastoma
Abstract: International audience; Although rare, glioblastoma is a devastating tumor of the central nervous system characterized by a poor survival and an extremely dark prognosis, making its diagnosis, treatment, and monitoring highly challenging. Numerous studies have highlighted extracellular vesicles (EVs) as key players of tumor growth, invasiveness, and resistance, as they carry oncogenic material. Moreover, EVs have been shown to communicate locally in a paracrine way but also at remote throughout the organism. Indeed, recent reports demonstrated the presence of brain tumor-derived EVs into body fluids such as plasma and cerebrospinal fluid. Fluid-associated EVs have indeed been suspected to reflect quantitative and qualitative information about the status and fate of the tumor and can potentially act as a resource for noninvasive biomarkers that might assist in diagnosis, treatment, and follow-up of glioblastoma patients. Here, we coined the name vesiclemia to define the concentration of plasmatic EVs, an intuitive term to be directly transposed in the clinical jargon.
Published: 2020
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10. Endothelial Cell-Cell Junctions in Tumor Angiogenesis

Author: Julie Gavard, Quentin Roux, Signaling in Oncogenesis, Angiogenesis and Permeability (CRCINA-ÉQUIPE 15), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA), Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), and Bernardo, Elizabeth
Subjects: Tumor angiogenesis, 0303 health sciences, Chemistry, [SDV.CAN]Life Sciences [q-bio]/Cancer, Cell junction, Endothelial stem cell, 03 medical and health sciences, 0302 clinical medicine, [SDV.CAN] Life Sciences [q-bio]/Cancer, 030220 oncology & carcinogenesis, Cancer research, ComputingMilieux_MISCELLANEOUS, 030217 neurology & neurosurgery, 030304 developmental biology
Abstract: International audience
Published: 2019
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11. Paracaspase MALT1 regulates glioma cell survival by controlling endo-lysosome homeostasis

Author: Nicolas Bidère, Tiphaine Douanne, Elizabeth Harford-Wright, An Thys, Ying Li, Clément Maghe, Carolina Alves Nicolau, Jean-Sebastien Frenel, Gwennan André-Grégoire, Julie Gavard, Kilian Trillet, Kathryn A Jacobs, Signaling in Oncogenesis, Angiogenesis and Permeability (CRCINA-ÉQUIPE 15), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA), Integrated Center for Oncology [Angers] (ICO), School of Life Sciences [Beijing, China], Tsinghua University [Beijing] (THU), This research was funded by Fondation pour la Recherche Medicale (Equipe labellisée DEQ20180339184), Fondation ARC contre le Cancer (JG PJA20171206146), Ligue nationale contre le cancer comités de Loire-Atlantique, Maine et Loire, Vendée, Ille-et-Vilaine (JG, NB), Région Pays de la Loire et Nantes Métropole under Connect Talent Grant (JG), and SIRIC ILIAD INCa-DGOS-Inserm_12558. KAJ received PhD fellowships from Nantes Métropole and Fondation ARC, TD received PhD fellowship from Nantes Métropole, GAG and AT hold postdoctoral fellowships from Fondation de France and Fondation ARC, respectively., Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), and Bernardo, Elizabeth
Subjects: Male, Apoptosis, Lymphocyte Activation, Mice, 0302 clinical medicine, glioma, Tumor Cells, Cultured, Homeostasis, 0303 health sciences, Gene knockdown, Mice, Inbred BALB C, Membranes & Traf- ficking, General Neuroscience, TOR Serine-Threonine Kinases, RNA-Binding Proteins, Articles, Paracaspase, Middle Aged, 3. Good health, Gene Expression Regulation, Neoplastic, medicine.anatomical_structure, Neoplastic Stem Cells, lysosome, mTOR, Female, Autophagy & Cell Death, Signal Transduction, Programmed cell death, protease Subject Categories Cancer, Mice, Nude, [SDV.CAN]Life Sciences [q-bio]/Cancer, Endosomes, Biology, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, [SDV.CAN] Life Sciences [q-bio]/Cancer, Glioma, Lysosome, medicine, Biomarkers, Tumor, Animals, Humans, Molecular Biology, PI3K/AKT/mTOR pathway, 030304 developmental biology, Aged, Cell Proliferation, General Immunology and Microbiology, MALT1, Autophagy, medicine.disease, Xenograft Model Antitumor Assays, Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein, Proteolysis, Cancer research, Lysosomes, 030217 neurology & neurosurgery
Abstract: International audience; Glioblastoma is one of the most lethal forms of adult cancer with a median survival of around 15 months. A potential treatment strategy involves targeting glioblastoma stem-like cells (GSC), which constitute a cell autonomous reservoir of aberrant cells able to initiate, maintain, and repopulate the tumor mass. Here, we report that the expression of the paracaspase mucosa-associated lymphoid tissue l (MALT1), a protease previously linked to antigen receptor-mediated NF-jB activation and B-cell lymphoma survival, inversely correlates with patient probability of survival. The knockdown of MALT1 largely impaired the expansion of patient-derived stem-like cells in vitro, and this could be recapitulated with pharmacological inhibitors, in vitro and in vivo. Blocking MALT1 protease activity increases the endo-lysosome abundance, impairs autophagic flux, and culminates in lysosomal-mediated cell death, concomitantly with mTOR inactiva-tion and dispersion from endo-lysosomes. These findings place MALT1 as a new druggable target involved in glioblastoma and unveil ways to modulate the homeostasis of endo-lysosomes.
Published: 2019
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12. Inhibition of mTOR in head and neck cancer cells alters endothelial cell morphology in a paracrine fashion

Author: Kilian Trillet, Alfredo Ribeiro-Silva, Andressa Duarte, Nicolas Bidère, Gwennan André-Grégoire, An Thys, Julie Gavard, Signaling in Oncogenesis, Angiogenesis and Permeability (CRCINA-ÉQUIPE 15), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA), Laboratory of Cancer Pathology, University of São Paulo (USP)-Ribeirao Preto Medical School, Centre René Gauducheau, Institut de Cancérologie de l'Ouest [Angers/Nantes] (UNICANCER/ICO), UNICANCER-UNICANCER, Connect Talent Pays-de-la-Loire, Nantes Metropole, Connect Talent, Region Pays-de-la-Loire, Ligue Contre le Cancer Comités Loire-Atlantique, Maine et Loire, Vendée, CAPES, Grant number: 88881.134829/2016-01, Fondation de France, Fondation ARC pour la Recherche sur le Cancer, Equipe Labellisée, Fondation pour la Recherche Médicale., Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), Universidade de São Paulo = University of São Paulo (USP)-Ribeirao Preto Medical School, and Bernardo, Elizabeth
Subjects: 0301 basic medicine, Cancer Research, Angiogenesis, [SDV.CAN]Life Sciences [q-bio]/Cancer, Biology, 03 medical and health sciences, chemistry.chemical_compound, Paracrine signalling, 0302 clinical medicine, [SDV.CAN] Life Sciences [q-bio]/Cancer, Paracrine Communication, medicine, Tumor Cells, Cultured, Humans, Viability assay, Molecular Biology, PI3K/AKT/mTOR pathway, Cell Proliferation, Tumor microenvironment, CÉLULAS ENDOTELIAIS, TOR Serine-Threonine Kinases, medicine.disease, Head and neck squamous-cell carcinoma, Endothelial stem cell, Vascular endothelial growth factor, 030104 developmental biology, chemistry, Head and Neck Neoplasms, 030220 oncology & carcinogenesis, Culture Media, Conditioned, Cancer research, Carcinoma, Squamous Cell, Endothelium, Vascular
Abstract: International audience; Head and neck squamous cell carcinoma (HNSCC) represent aggressive classes of tumors with a high mortality rate. The mammalian target of rapamycin (mTOR) pathway is instrumental in their initiation and expansion. Although results from pre-clinical models promise mTOR targeting as a potent novel therapeutic approach, its impact on the tumor microenvironment, such as endothelial cells is only scarcely investigated. Here, we first confirmed the effects of mTOR pharmacological inhibition on cell viability, clonogenicity, and proliferation in HNSCC human cell lines, HN26, and HN30. While Everolimus and Torin1 potently blunted mTOR-based proliferation of HN26 and HN30 lines, endothelial cells were left intact. To further explore the possibility of a paracrine bystander action of HNSCC-treated cells on endothelial cells, conditioned medium from Everolimus-and Torin1-challenged HN26 and HN30 cells were collected and applied to naive human endothelial cells. Although endothelial cell viability was again not modified, morphology and mobility were changed. Indeed, spreading of endothelial cells was altered upon challenge with mTOR-pretreated tumor conditioned-media, as measured via cell impedance and imagery. Interestingly, this was associated with an augmentation of focal adhesion kinase (FAK) active phosphorylation and enhanced migratory behavior. From a molecular standpoint, the production of vascular endothelial growth factor was elevated in treated HNSCC cells and might contribute to FAK phosphorylation. Although mTOR inhibition in tumor cells did hinder their growth, it also favors the release of factors that subsequently enable endothelial cell migration. Further studies will address how this paracrine action may affect tumor-driven angiogenesis upon pharmacological treatments. K E Y W O R D S adhesion, head and neck cancer, mTOR, signaling pathway
Published: 2019
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13. Temozolomide affects Extracellular Vesicles Released by Glioblastoma Cells

Author: Gwennan André-Grégoire, Nicolas Bidère, Julie Gavard, Signaling in Oncogenesis, Angiogenesis and Permeability (CRCINA-ÉQUIPE 15), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA), Institut de Cancérologie de l'Ouest [Angers/Nantes] (UNICANCER/ICO), UNICANCER, This research was funded by a postdoctoral fellowship from Fondation de France (G.A.G), Ligue contre le cancer comités Loire-Atlantique et Vendée (J.G), Connect Talent Grant from Region Pays de la Loire et Nantes Metropole (J.G)., Bernardo, Elizabeth, and Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)
Subjects: 0301 basic medicine, Proteomics, Male, [SDV.CAN]Life Sciences [q-bio]/Cancer, Biochemistry, Exosome, Extracellular vesicles, 03 medical and health sciences, Extracellular Vesicles, [SDV.CAN] Life Sciences [q-bio]/Cancer, Glioma, Cell Line, Tumor, medicine, Cell Adhesion, Temozolomide, Humans, Cell adhesion, Chemistry, Brain Neoplasms, Vesicle, Brain tumour, General Medicine, medicine.disease, In vitro, 3. Good health, 030104 developmental biology, Homogeneous, Cancer research, Neoplastic Stem Cells, Female, Glioblastoma, medicine.drug
Abstract: International audience; Glioblastoma multiforme (GBM) is the most aggressive primary tumour within the brain as well as the most common and lethal cerebral cancer, mainly because of treatment failure. Indeed, tumour recurrence is inevitable and fatal in a short period of time. Glioblastoma stem-like cells (GSCs) are thought to participate in tumour initiation, expansion, resistance to treatments, including to the alkylating chemotherapeutic agent temozolomide, and relapse. Here, we assessed whether extracellular vesicles (EVs) released by GSCs could disseminate factors involved in resistance mechanisms. We first characterized EVs either circulating in peripheral blood from newly diagnosed patients or released by patient-derived temozolomide-resistant GSCs. We found that EVs from both sources were mainly composed of particles homogeneous in size (50e100 nm), while they were more abundant in liquid biopsies from GBM patients, as compared to healthy donors. Further, mass spectrometry analysis from GSC-derived EVs unveiled that particles from control and temozolomide-treated cells share core components of EVs, as well as ribosome-and proteasome-associated networks. More strikingly, temozolomide treatment led to the enrichment of EVs with cargoes dedicated to cell adhesion processes. Thus, while relatively inefficient in killing GSCs in vitro, temozolomide could instead increase the release of pro-tumoral information.
Published: 2017
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14. Vaisseaux sanguins et tumeurs ou l’art du dialogue

Author: Sandy Azzi and Julie Gavard
Subjects: Tumor angiogenesis, General Medicine, Tumor initiation, Biology, medicine.disease_cause, General Biochemistry, Genetics and Molecular Biology, Crosstalk (biology), medicine.anatomical_structure, Cancer cell, medicine, Cancer research, Vascular niche, Carcinogenesis, Blood vessel
Abstract: Tumor initiation and progression is a complex process in which cells acquire aberrant proliferation, survival and migration properties, and the ability to form a dedicated blood vessel network. Recent studies highlighted the existence of an active crosstalk between endothelial cells and the tumor mass. Indeed, cancer stem-like cells have been identified and found in the vicinity of blood vessels, and the latter has been proposed to act as a feeding bed for tumors, especially governing the fate of cancer stem-like cells. Here, we present an overview of the direct interplay between endothelial and cancer cells. We will first introduce the mechanisms involved in tumor angiogenesis. How the microenvironment impacts on endothelial plasticity will next be detailed, focusing on the tumor main secreted factors. Finally, the role of the vascular niche and its angiocrine factors in tumorigenesis will be addressed.
Published: 2014
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15. Critical multiple angiogenic factors secreted by glioblastoma stem-like cells underline the need for combinatorial anti-angiogenic therapeutic strategies

Author: Julie Gavard, Marie-Pierre Junier, Cécile Thirant, Hervé Chneiweiss, Plasticité gliale et neuro-oncologie = Glial Plasticity (NPS-04), Neurosciences Paris Seine (NPS), 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)-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)-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)-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), Neuroscience Paris Seine (NPS), 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)-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 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)-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), Centre National de la Recherche Scientifique (CNRS)-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)-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)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie Paris Seine (IBPS), and 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)-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)-Université Pierre et Marie Curie - Paris 6 (UPMC)
Subjects: Anti-angiogenic, medicine.medical_treatment, Clinical Biochemistry, Angiogenesis Inhibitors, Biology, Tumor vasculature, 03 medical and health sciences, 0302 clinical medicine, Endothelial cell, Semaphorin, HDGF, medicine, Humans, Primary Brain Tumors, 030304 developmental biology, 0303 health sciences, Growth factor, Anti angiogenic, Therapeutic resistance, medicine.disease, 3. Good health, Endothelial stem cell, Glioblastoma stem-like cells, 030220 oncology & carcinogenesis, Immunology, Neoplastic Stem Cells, Cancer research, Intercellular Signaling Peptides and Proteins, Angiogenesis Inducing Agents, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Glioblastoma
Abstract: International audience; Glioblastomas are the most frequent adult primary brain tumors that still remain fatal despite major clinical efforts. As in other solid tumors, populations of glioblastoma stem-like cells (GSCs) endowed with tumor initiating and therapeutic resistance properties have been identified. Glioblastomas are highly vascularized tumors resulting in a rich dialog between GSCs and endothelial cells. In one direction, endothelial cells and their secreted proteins are able to sustain GSC properties while, in turn, GSCs can promote neoangiogenesis, modulate endothelial cell functions and may even transdifferentiate into endothelial cells. Accordingly, targeting tumor vasculature seems a promising issue despite incomplete and transient results obtained from anti-vascular endothelial growth factor therapeutic trials. Recent findings of novel GSC-secreted molecules with pro-angiogenic properties (Semaphorin 3A, hepatoma-derived growth factor) open the path to the design of a concerted attack of glioblastoma vasculature that could overcome the development of resistance to single-targeted therapies while keeping away the toxicity of the treatments.
Published: 2013
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16. β-escin selectively targets the glioblastoma-initiating cell population and reduces cell viability

Author: Julie Gavard, Nicolas Bidère, Elizabeth Harford-Wright, Signaling in Oncogenesis, Angiogenesis and Permeability (CRCINA-ÉQUIPE 15), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA), This research was funded by a grant from RégionPays-de-la-Loire and Nantes Metropole (Connect Talent),Ligue Nationale contre le Cancer (comité Pays de laLoire, Maine-et-Loire et Sarthe), Fondation ARC pour laRecherche contre le Cancer. EHW was a recipient of aCanceropole île-de-France fellowship, Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), and Bernardo, Elizabeth
Subjects: 0301 basic medicine, Male, Programmed cell death, Cell Survival, Population, Cell, [SDV.CAN]Life Sciences [q-bio]/Cancer, temozolomide, Biology, self-renewal, 03 medical and health sciences, 0302 clinical medicine, [SDV.CAN] Life Sciences [q-bio]/Cancer, Cell Line, Tumor, chemical screen, medicine, Tumor Cells, Cultured, Cytotoxic T cell, Humans, Viability assay, Progenitor cell, Cell Self Renewal, education, Aged, Cell Proliferation, education.field_of_study, Escin, Temozolomide, Molecular Structure, Brain Neoplasms, glioblastoma-initiating cells, apoptosis, Middle Aged, 3. Good health, 030104 developmental biology, medicine.anatomical_structure, Oncology, Apoptosis, 030220 oncology & carcinogenesis, Immunology, Cancer research, Neoplastic Stem Cells, Female, Glioblastoma, medicine.drug, Research Paper
Abstract: International audience; Glioblastoma multiforme (GBM) is a highly aggressive tumour of the central nervous system and is associated with an extremely poor prognosis. Within GBM exists a subpopulation of cells, glioblastoma-initiating cells (GIC), which possess the characteristics of progenitor cells, have the ability to initiate tumour growth and resist to current treatment strategies. We aimed at identifying novel specific inhibitors of GIC expansion through use of a large-scale chemical screen of approved small molecules. Here, we report the identification of the natural compound β-escin as a selective inhibitor of GIC viability. Indeed, β-escin was significantly cytotoxic in nine patient-derived GIC, whilst exhibiting no substantial effect on the other human cancer or control cell lines tested. In addition, β-escin was more effective at reducing GIC growth than current clinically used cytotoxic agents. We further show that β-escin triggers caspase-dependent cell death combined with a loss of stemness properties. However, blocking apoptosis could not rescue the β-escin-induced reduction in sphere formation or stemness marker activity, indicating that β-escin directly modifies the stem identity of GIC, independent of the induction of cell death. Thus, this study has repositioned β-escin as a promising potential candidate to selectively target the aggressive population of initiating cells within GBM.
Published: 2016
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17. Targeted Killing of Cancer Cells in Vivo and in Vitro with EGF-Directed Carbon Nanotube-Based Drug Delivery

Author: Ashwin Bhirde, Richard D. Leapman, Guofeng Zhang, Alioscka A. Sousa, Vyomesh Patel, Andrius Masedunskas, James F. Rusling, Julie Gavard, J. Silvio Gutkind, and Roberto Weigert
Subjects: Materials science, General Physics and Astronomy, Carbon nanotubes in medicine, Antineoplastic Agents, Pharmacology, Article, Substrate Specificity, Mice, Drug Delivery Systems, Epidermal growth factor, In vivo, Cell Line, Tumor, medicine, Animals, Humans, Tissue Distribution, General Materials Science, Cell Proliferation, Cisplatin, Epidermal Growth Factor, Nanotubes, Carbon, General Engineering, Squamous carcinoma, ErbB Receptors, Gene Expression Regulation, Neoplastic, Targeted drug delivery, Head and Neck Neoplasms, Cancer cell, Drug delivery, Carcinoma, Squamous Cell, Cancer research, Female, medicine.drug
Abstract: Carbon nanotube-based drug delivery holds great promise for cancer therapy. Herein we report the first targeted, in vivo killing of cancer cells using a drug-single wall carbon nanotube (SWNT) bioconjugate, and demonstrate efficacy superior to non-targeted bioconjugates. First line anti-cancer agent cisplatin and epidermal growth factor (EGF) were attached to SWNTs to specifically target squamous cancer, and the non-targeted control was SWNT-cisplatin without EGF. Initialin vitro imaging studies with head and neck squamous carcinoma cells (HNSCC) overexpressing EGF receptors (EGFR) using Qdot luminescence and confocal microscopy showed that SWNT-Qdot-EGF bioconjugates internalized rapidly into the cancer cells. Limited uptake occurred for control cells without EGF, and uptake was blocked by siRNA knockdown of EGFR in cancer cells, revealing the importance of EGFEGFR binding. Three color, two-photon intra-vital video imagingin vivo showed that SWNT-Qdot-EGF injected into live mice was selectively taken up by HNSCC tumors, but SWNT-Qdot controls with no EGF were cleared from the tumor region in
Published: 2009
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18. Extracellular vesicle-transported Semaphorin3A promotes vascular permeability in glioblastoma

Author: Eva María Galán-Moya, Sandy Azzi, Damien Ricard, A Citerne, Nicolas Bidère, Elizabeth Harford-Wright, Lucas Treps, Alain Schmitt, Sébastien Edmond, Julie Gavard, Institut Cochin ( UM3 (UMR 8104 / U1016) ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Hôpital d'Instruction des Armées du Val de Grâce, Service de Santé des Armées, Centre de Recherche en Cancérologie / Nantes - Angers ( CRCNA ), CHU Angers-Hôtel-Dieu de Nantes-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Hôpital Laennec-Centre National de la Recherche Scientifique ( CNRS ) -Faculté de Médecine d'Angers-Centre hospitalier universitaire de Nantes ( CHU Nantes ), SOAP - Signaling in Oncogenesis, Angiogenesis and Permeability ( Equipe 15 ), CHU Angers-Hôtel-Dieu de Nantes-Hôpital Laennec-Centre National de la Recherche Scientifique ( CNRS ) -Centre de Recherche en Cancérologie/Nantes - Angers ( CRCNA ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Cognition and Action Group ( COGNAC-G - UMR 8257 ), Centre National de la Recherche Scientifique ( CNRS ) -Université Paris Descartes - Paris 5 ( UPD5 ) -École normale supérieure - Cachan ( ENS Cachan ), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherche en Cancérologie Nantes-Angers (CRCNA), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM)-Hôtel-Dieu de Nantes-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôpital Laennec-Centre National de la Recherche Scientifique (CNRS)-Faculté de Médecine d'Angers-Centre hospitalier universitaire de Nantes (CHU Nantes), Signaling in Oncogenesis, Angiogenesis and Permeability (CRCINA-ÉQUIPE 15), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA), Cognition and Action Group (COGNAC-G - UMR 8257), École normale supérieure - Cachan (ENS Cachan)-Université Paris Descartes - Paris 5 (UPD5)-Centre National de la Recherche Scientifique (CNRS), Bernardo, Elizabeth, Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), and Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)
Subjects: Male, 0301 basic medicine, Cancer Research, Vascular permeability, [SDV.CAN]Life Sciences [q-bio]/Cancer, Biology, Bioinformatics, [ SDV.CAN ] Life Sciences [q-bio]/Cancer, Capillary Permeability, Extracellular Vesicles, Mice, 03 medical and health sciences, [SDV.CAN] Life Sciences [q-bio]/Cancer, In vivo, Cell Line, Tumor, Neuropilin 1, Genetics, Animals, Humans, Receptor, Molecular Biology, Aged, Aged, 80 and over, Semaphorin-3A, SEMA3A, Extracellular vesicle, Middle Aged, Neuropilin-1, In vitro, 3. Good health, Protein Transport, 030104 developmental biology, Permeability (electromagnetism), Cancer research, Female, Endothelium, Vascular, Glioblastoma
Abstract: International audience; Glioblastoma are malignant highly vascularized brain tumours, which feature large oedema resulting from tumour-promoted vascular leakage. The pro-permeability factor Semaphorin3A (Sema3A) produced within glioblastoma has been linked to the loss of endothelial barrier integrity. Here, we report that extracellular vesicles (EVs) released by patient-derived glioblastoma cells disrupt the endothelial barrier. EVs expressed Sema3A at their surface, which accounted for in vitro elevation of brain endothelial permeability and in vivo vascular permeability, in both skin and brain vasculature. Blocking Sema3A or its receptor Neuropilin1 (NRP1) hampered EV-mediated permeability. In vivo models using ectopically and orthotopically xenografted mice revealed that Sema3A-containing EVs were efficiently detected in the blood stream. In keeping with this idea, sera from glioblastoma multiforme (GBM) patients also contain high levels of Sema3A carried in the EV fraction that enhanced vascular permeability, in a Sema3A/ NRP1-dependent manner. Our results suggest that EV-delivered Sema3A orchestrates loss of barrier integrity in glioblastoma and may be of interest for prognostic purposes.
Published: 2016
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19. Luteolin Impacts on the DNA Damage Pathway in Oral Squamous Cell Carcinoma

Author: Kellen Cristine Tjioe, Denise Tostes Oliveira, Julie Gavard, Institut Cochin (IC UM3 (UMR 8104 / U1016)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Department of stomatology, University of São Paulo (USP), Centre de Recherche en Cancérologie Nantes-Angers (CRCNA), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM)-Hôtel-Dieu de Nantes-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôpital Laennec-Centre National de la Recherche Scientifique (CNRS)-Faculté de Médecine d'Angers-Centre hospitalier universitaire de Nantes (CHU Nantes), This research was funded by Fondation pour la RechercheMedicale, Institut National du Cancer INCA_6508, Liguenationale contre le cancer comite de Loire-Atlantique andSarthe, Region Pays-de-la-Loire, Nantes Metropole, and Coordenacaode Aperfeicoamento de Pessoal de Nivel Superior ¸(#2788-13-6)., Bernardo, Elizabeth, Universidade de São Paulo = University of São Paulo (USP), Institut Cochin ( UM3 (UMR 8104 / U1016) ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), University of São Paulo ( USP ), Centre de Recherche en Cancérologie / Nantes - Angers ( CRCNA ), and CHU Angers-Centre hospitalier universitaire de Nantes ( CHU Nantes ) -Hôtel-Dieu de Nantes-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Hôpital Laennec-Centre National de la Recherche Scientifique ( CNRS ) -Faculté de Médecine d'Angers
Subjects: 0301 basic medicine, Cancer Research, DNA repair, DNA damage, Medicine (miscellaneous), Antineoplastic Agents, [SDV.CAN]Life Sciences [q-bio]/Cancer, Biology, Pharmacology, [ SDV.CAN ] Life Sciences [q-bio]/Cancer, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, [SDV.CAN] Life Sciences [q-bio]/Cancer, Cell Line, Tumor, medicine, Humans, Epidermal growth factor receptor, Luteolin, Cisplatin, Nutrition and Dietetics, Dose-Response Relationship, Drug, ANTINEOPLÁSICOS, Cancer, Tyrphostins, Nitro Compounds, medicine.disease, 3. Good health, Thiazoles, stomatognathic diseases, HaCaT, 030104 developmental biology, Oncology, chemistry, 030220 oncology & carcinogenesis, Thioxanthenes, Cancer cell, Carcinoma, Squamous Cell, biology.protein, Drug Therapy, Combination, Mouth Neoplasms, DNA Damage, medicine.drug
Abstract: International audience; Oral squamous cell carcinoma (OSCC) exhibited high chemoresistance to current treatments. Here weaimed at identifying and repositioning approved drugs that could be selectively toxic toward OSCCcells. Through a cell-based drug screening of 1,280 chemical molecules, we selected compounds lethalto oral cancer SCC-25 cells, while sparing normal keratinocyte HaCaT cells. Within the chemical library,the natural flavonoid luteolin was identified as a potent cytotoxic agent against oral cancer cells invitro, along with metixene hydrochloride and nitazoxanide. Of note, they exhibit low toxicity and highefficiency compared to the standard-of-care, such as cisplatin and the epidermal growth factorreceptor inhibitor tyrphostin. From a molecular standpoint, luteolin causes phosphorylation of ataxiatelangiectasia mutated (ATM) and H2AX in a DNA repair pathway and can be efficiently combinedwith a checkpoint kinase (CHK) pharmacological inhibitor. Thus, luteolin emerges as a potent cytotoxicand/or adjuvant therapy in oral cancer, as it is a natural compound presenting better effects in vitrocompared to conventional chemotherapeutic agents. Future in vivo exploration is next required toprovide the proof-of-concept that luteolin could be an efficient anticancer molecule.
Published: 2016
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20. Desert Hedgehog/Patch2 Axis Contributes to Vascular Permeability and Angiogenesis in Glioblastoma

Author: Hai-Mi Ngo, Julie Gavard, Lucas Treps, Elizabeth Harford-Wright, Sandy Azzi, Héloïse M. Leclair, Institut Cochin (IC UM3 (UMR 8104 / U1016)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre de Recherche en Cancérologie Nantes-Angers (CRCNA), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM)-Hôtel-Dieu de Nantes-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôpital Laennec-Centre National de la Recherche Scientifique (CNRS)-Faculté de Médecine d'Angers-Centre hospitalier universitaire de Nantes (CHU Nantes), This research was funded by:Liguenationalecontrelecancer,InstitutNationalduCancer,RegionPays-de-la-Loire, andNantes Metropole. SA and LT are supported byfellowships fromFondation ARC Association pour la Recherche surle CancerandUniversite Paris Descartes, respectively., Bos, Mireille, Institut Cochin ( UM3 (UMR 8104 / U1016) ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Centre de Recherche en Cancérologie / Nantes - Angers ( CRCNA ), and CHU Angers-Hôtel-Dieu de Nantes-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Hôpital Laennec-Centre National de la Recherche Scientifique ( CNRS ) -Faculté de Médecine d'Angers-Centre hospitalier universitaire de Nantes ( CHU Nantes )
Subjects: Angiogenesis, hedgehog, brain endothelial cells, Vascular permeability, Biology, Bioinformatics, Paracrine signalling, Glioma, glioma, medicine, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Gene silencing, Pharmacology (medical), [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Hedgehog, [ SDV.BBM ] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Desert hedgehog, Original Research, Pharmacology, lcsh:RM1-950, Hedghog, medicine.disease, Endothelial stem cell, tumor vasculature, lcsh:Therapeutics. Pharmacology, Cancer research, permeability
Abstract: International audience; Glioblastoma multiforme (GBM) constitutes the most common and the most aggressive type of human tumors affecting the central nervous system. Prognosis remains dark due to the inefficiency of current treatments and the rapid relapse. Paralleling other human tumors, GBM contains a fraction of tumor initiating cells with the capacity to self-renew, initiate and maintain the tumor mass. These cells were found in close proximity to brain vasculature, suggesting functional interactions between brain tumor-initiating cells (BTICs) and endothelial cells within the so-called vascular niche. However, the mechanisms by which these cells impact on the endothelium plasticity and function remain unclear. Using culture of BTICs isolated from a cohort of 14 GBM patients, we show that BTICs secretome promotes brain endothelial cell remodeling in a VEGF-independent manner. Gene array analysis unmasked that BTICs-released factors drove the expression of Ptch2 in endothelial cells. Interestingly, BTICs produce desert hedgehog (DHH) ligand, enabling a paracrine DHH/Ptch2 signaling cascade that conveys elevated permeability and angiogenesis. Finally, DHH silencing in BTICs dramatically reduced tumor growth, as well as vascularization and intra-tumor permeability. Collectively, our data unveil a role for DHH in exacerbated tumor angiogenesis and permeability, which may ultimately favor glioblastoma growth, and thus place the DHH/Ptch2 nexus as a molecular target for novel therapies.
Published: 2015
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21. L'angiogenèse tumorale Quand l'arbre de vie tourne mal

Author: Lucas Treps, Julie Gavard, Institut Cochin (IC UM3 (UMR 8104 / U1016)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre de Recherche en Cancérologie Nantes-Angers (CRCNA), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM)-Hôtel-Dieu de Nantes-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôpital Laennec-Centre National de la Recherche Scientifique (CNRS)-Faculté de Médecine d'Angers-Centre hospitalier universitaire de Nantes (CHU Nantes), and Les recherches reçoivent le support de la Ligue nationale contre le cancer, l’INCA, la Fondation pour la recherche médicale, la Région Pays-de-La-Loire, et Nantes-Métropole.
Subjects: Tumor angiogenesis, Vessel network, Angiogenesis, [SDV.CAN]Life Sciences [q-bio]/Cancer, General Medicine, Biology, Tumor vasculature, medicine.disease_cause, General Biochemistry, Genetics and Molecular Biology, 3. Good health, Neovascularization, medicine.anatomical_structure, Tumor progression, medicine, Cancer research, medicine.symptom, Carcinogenesis, Blood vessel
Abstract: International audience; Angiogenesis is a highly controlled multistep process that allows the formation of a harmonious vascular network during embryonic development and in adults. In addition, tumor progression also involves a dedicated blood vessel supply to fuel the tumor mass, pirating physiological molecular and cellular mechanisms. However, tumor angiogenesis is a quite inefficient process, as perfusion is not optimal, vessel integrity is not guaranteed, and vessel network is irrationally organized. While fundamental molecular and cellular mechanisms have been the field of intense investigation, anticancer therapies have evolved with the possibility to target tumor angiogenesis. This review presents the different steps involved in the formation of normal and tumor angiogenesis, and how tumor vasculature abnormalities could contribute to tumorigenesis and conventional therapy failure.
Published: 2015
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22. YGLF motif in the Kaposi sarcoma herpes virus G-protein- coupled receptor adjusts NF-kB activation and paracrine actions

Author: Julie Dwyer, C Alexia, N Bidère, Nicolas Dupin, Julie Gavard, Jagoda K. Hebda, Héloïse M. Leclair, Sandy Azzi, S S Smith, Institut Cochin (UM3 (UMR 8104 / U1016)), Université Paris Descartes - Paris 5 (UPD5) - Institut National de la Santé et de la Recherche Médicale (INSERM) - Centre National de la Recherche Scientifique (CNRS), Université Paris-Sud - Paris 11 (UP11), Régulation de la survie cellulaire et des allogreffes, Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Cochin [AP-HP], Laboratoire de Physique Théorique d'Orsay [Orsay] (LPT), Université Paris-Sud - Paris 11 (UP11) - Centre National de la Recherche Scientifique (CNRS), Bos, Mireille, Institut Cochin (IC UM3 (UMR 8104 / U1016)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université Paris-Sud - Paris 11 (UP11)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Université Paris-Sud - Paris 11 (UP11), and Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: Cancer Research, viruses, Amino Acid Motifs, HIV Infections, KSHV, Biology, Jurkat cells, Receptors, G-Protein-Coupled, Proinflammatory cytokine, Jurkat Cells, Open Reading Frames, Paracrine signalling, Cell Movement, trafficking, Genetics, medicine, B-lymphocytes, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, NF-kB, RNA, Small Interfering, Receptor, Sarcoma, Kaposi, Molecular Biology, G protein-coupled receptor, Inflammation, Binding Sites, Cell Membrane, HEK 293 cells, NF-kappa B p50 Subunit, virus diseases, vGPCR, Flow Cytometry, medicine.disease, Virology, Clathrin, 3. Good health, HEK293 Cells, Herpesvirus 8, Human, Mutation, Leukocytes, Mononuclear, Cancer research, Cytokines, Primary effusion lymphoma, Signal transduction, HeLa Cells, Signal Transduction, HIV malignancies
Abstract: International audience; Kaposi sarcoma (KS) and primary effusion lymphoma (PEL) are two pathologies associated with KS herpes virus (KSHV/HHV-8) infection. KSHV genome contains several oncogenes, among which, the viral G-protein-coupled receptor (vGPCR open reading frame 74) has emerged as a major factor in KS pathogenicity. Indeed, vGPCR is a constitutively active receptor, whose expression is sufficient to drive cell transformation in vitro and tumour development in mice. However, neither the role of vGPCR in KSHV-infected B-lymphocytes nor the molecular basis for its constitutive activation is well understood. Here, we show that vGPCR expression contributes to nuclear factor-kB (NF-kB)-dependent cellular survival in both PEL cells and primary B cells from HIV-negative KS patients. We further identified within vGPCR an AP2 consensus binding motif, Y 326 GLF, that directs its localization between the plasma membrane and clathrin-coated vesicles. The introduction of a mutation in this site (Y 326 A) increased NF-kB activity and proinflammatory cytokines production. This correlated with exacerbated morphological rearrangement, migration and proliferation of non-infected monocytes. Collectively, our work raises the possibility that KSHV-infected B-lymphocytes use vGPCR to impact ultimately the immune response and communication within the tumour microenvironment in KSHV-associated pathologies.
Published: 2013
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23. Vascular Permeability and Drug Delivery in Cancers

Author: Julie Gavard, Sandy Azzi, and Jagoda K. Hebda
Subjects: Cancer Research, Pathology, medicine.medical_specialty, Angiogenesis, endothelial barrier, Vascular permeability, Context (language use), Review Article, lcsh:RC254-282, chemistry.chemical_compound, VE-cadherin, medicine, Tissue homeostasis, business.industry, tumor angiogenesis, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, VEGF, Extravasation, Vascular endothelial growth factor, medicine.anatomical_structure, Oncology, chemistry, Tumor progression, Cancer research, permeability, business, Blood vessel
Abstract: The endothelial barrier strictly maintains vascular and tissue homeostasis, and therefore modulates many physiological processes such as angiogenesis, immune responses, and dynamic exchanges throughout organs. Consequently, alteration of this finely tuned function may have devastating consequences for the organism. This is particularly obvious in cancers, where a disorganized and leaky blood vessel network irrigates solid tumors. In this context, vascular permeability drives tumor-induced angiogenesis, blood flow disturbances, inflammatory cell infiltration, and tumor cell extravasation. This can directly restrain the efficacy of conventional therapies by limiting intravenous drug delivery. Indeed, for more effective anti-angiogenic therapies, it is now accepted that not only should excessive angiogenesis be alleviated, but also that the tumor vasculature needs to be normalized. Recovery of normal state vasculature requires diminishing hyperpermeability, increasing pericyte coverage, and restoring the basement membrane, to subsequently reduce hypoxia and interstitial fluid pressure. In this review, we will introduce how vascular permeability accompanies tumor progression and, as a collateral damage, impacts on efficient drug delivery. The molecular mechanisms involved in tumor-driven vascular permeability will next be detailed, with a particular focus on the main factors produced by tumor cells, especially the emblematic vascular endothelial growth factor (VEGF). Finally, new perspectives in cancer therapy will be presented, centered on the use of anti-permeability factors and normalization agents.
Published: 2013
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24. Differential Proteomic Analysis of Human Glioblastoma and Neural Stem Cells Reveals HDGF as a Novel Angiogenic Secreted Factor

Author: Fabrice Soncin, Julie Gavard, Luiz Gustavo Dubois, Cécile Thirant, Cédric Broussard, Sébastien Pinte, Bertrand Devaux, Pascale Varlet, Hervé Chneiweiss, Philippe Chafey, Eva María Galán-Moya, Marie-Pierre Junier, Plasticité gliale et neuro-oncologie = Glial Plasticity (NPS-04), Neurosciences Paris Seine (NPS), 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)-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 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)-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), ARC, Region Ile de France-Canceropole, Neuroscience Paris Seine (NPS), Centre National de la Recherche Scientifique (CNRS)-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)-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)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie Paris Seine (IBPS), and 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)-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)-Université Pierre et Marie Curie - Paris 6 (UPMC)
Subjects: Male, Proteomics, medicine.medical_treatment, Tumor initiation, Mice, 0302 clinical medicine, Neural Stem Cells, Cell Movement, Tumor Cells, Cultured, Secreted factor, Neoangiogenesis, 0303 health sciences, Neovascularization, Pathologic, Cancer stem cells, Tumor progression, Neural stem cell, 3. Good health, 030220 oncology & carcinogenesis, Intercellular Signaling Peptides and Proteins, Molecular Medicine, Female, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Adult, endocrine system, Transplantation, Heterologous, Adult glioma, Biology, 03 medical and health sciences, Cancer stem cell, Glioma, medicine, Animals, Humans, 030304 developmental biology, Growth factor, fungi, Endothelial Cells, Cell Biology, Two-dimensional differential gel electrophoresis, medicine.disease, Molecular biology, Transplantation, Culture Media, Conditioned, Cancer cell, Cancer research, Angiogenesis Inducing Agents, Glioblastoma, Neoplasm Transplantation, Developmental Biology
Abstract: International audience; Presence in glioblastomas of cancer cells with normal neural stem cell (NSC) properties, tumor initiating capacity, and resistance to current therapies suggests that glioblastoma stem-like cells (GSCs) play central roles in glioblastoma development. We cultured human GSCs endowed with all features of tumor stem cells, including tumor initiation after xenograft and radio-chemoresistance. We established proteomes from four GSC cultures and their corresponding whole tumor tissues (TTs) and from human NSCs. Two-dimensional difference gel electrophoresis and tandem mass spectrometry revealed a twofold increase of hepatoma-derived growth factor (HDGF) in GSCs as compared to TTs and NSCs. Western blot analysis confirmed HDGF overexpression in GSCs as well as its presence in GSC-conditioned medium, while, in contrast, no HDGF was detected in NSC secretome. At the functional level, GSC-conditioned medium induced migration of human cerebral endothelial cells that can be blocked by anti-HDGF antibodies. In vivo, GSC-conditioned medium induced neoangiogenesis, whereas HDGF-targeting siRNAs abrogated this effect. Altogether, our results identify a novel candidate, by which GSCs can support neoangiogenesis, a high-grade glioma hallmark. Our strategy illustrates the usefulness of comparative proteomic analysis to decipher molecular pathways, which underlie GSC properties. STEM CELLS 2012;30:845853
Published: 2012
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25. Glioblastoma cell-secreted interleukin-8 induces brain endothelial cell permeability via CXCR2

Author: Julie Dwyer, Sandy Azzi, Julie Gavard, Armelle Le Guelte, Nicolas Bidère, Sherri S. Smith, Eva María Galán-Moya, and Jagoda K. Hebda
Subjects: Chemokine, Pathology, medicine.medical_specialty, Endothelium, Angiogenesis, Science, Cancer Treatment, Vascular permeability, Biology, Receptors, Interleukin-8B, Capillary Permeability, Cell Line, Tumor, Molecular Cell Biology, Basic Cancer Research, medicine, Cell Adhesion, Humans, Membrane Receptor Signaling, CXC chemokine receptors, Interleukin 8, Neurological Tumors, neoplasms, Oncogenic Signaling, Multidisciplinary, Brain Neoplasms, Interleukin-8, Endothelial Cells, Cancers and Neoplasms, Signaling in Selected Disciplines, Cadherins, nervous system diseases, Endothelial stem cell, Gene Expression Regulation, Neoplastic, medicine.anatomical_structure, Oncology, Cell culture, Culture Media, Conditioned, biology.protein, Cancer research, Medicine, Antiangiogenesis Therapy, Cellular Types, Glioblastoma, Glioblastoma Multiforme, Research Article, Signal Transduction
Abstract: Glioblastoma constitutes the most aggressive and deadly of brain tumors. As yet, both conventional and molecular-based therapies have met with limited success in treatment of this cancer. Among other explanations, the heterogeneity of glioblastoma and the associated microenvironment contribute to its development, as well as resistance and recurrence in response to treatments. Increased vascularity suggests that tumor angiogenesis plays an important role in glioblastoma progression. However, the molecular crosstalk between endothelial and glioblastoma cells requires further investigation. To examine the effects of glioblastoma-derived signals on endothelial homeostasis, glioblastoma cell secretions were collected and used to treat brain endothelial cells. Here, we present evidence that the glioblastoma secretome provides pro-angiogenic signals sufficient to disrupt VE-cadherin-mediated cell-cell junctions and promote endothelial permeability in brain microvascular endothelial cells. An unbiased angiogenesis-specific antibody array screen identified the chemokine, interleukin-8, which was further demonstrated to function as a key factor involved in glioblastoma-induced permeability, mediated through its receptor CXCR2 on brain endothelia. This underappreciated interface between glioblastoma cells and associated endothelium may inspire the development of novel therapeutic strategies to induce tumor regression by preventing vascular permeability and inhibiting angiogenesis.
Published: 2012

26. Remodeling of VE-cadherin junctions by the human herpes virus 8 G-protein coupled receptor

Author: Julie Gavard, M Sumbal, E M Galan Moya, Nicolas Dupin, Julie Dwyer, Jorge S. Gutkind, L Douguet, Philippe Grange, A Le Guelte, and Agnès Carlotti
Subjects: Cancer Research, Indoles, Skin Neoplasms, Pyridines, medicine.disease_cause, Cell junction, Mice, Phosphatidylinositol 3-Kinases, 0302 clinical medicine, Enzyme Inhibitors, RNA, Small Interfering, Receptor, Skin, 0303 health sciences, Gene knockdown, Sulfonamides, Cadherins, 3. Good health, Intercellular Junctions, 030220 oncology & carcinogenesis, Herpesvirus 8, Human, Female, Receptors, Chemokine, Wortmannin, Morpholines, Mice, Nude, Biology, Virus, Cell Line, Capillary Permeability, 03 medical and health sciences, Antigens, CD, Quinoxalines, Genetics, medicine, Animals, Humans, Furans, Molecular Biology, Sarcoma, Kaposi, 030304 developmental biology, G protein-coupled receptor, Acquired Immunodeficiency Syndrome, Cadherin, Endothelial Cells, Androstadienes, Pyrimidines, Chromones, Cinnamates, Immunology, Cancer research, Thiazolidinediones, VE-cadherin, Carcinogenesis
Abstract: Kaposi Sarcoma (KS) are opportunistic tumors, associated with human herpes virus 8 (HHV8) infection. KS development is highly favored by immune-depression and remains the second most frequent tumor in acquired immune deficiency syndrome patients. Although it has been shown that experimental expression of the HHV8 G-protein-coupled receptor (vGPCR) in the endothelial compartment is alone sufficient to recapitulate the formation and progression of KS-like lesions, its functional effects on endothelial homeostasis are not fully understood. Here we show that vGPCR expression in endothelial cells induces an increase in paracellular permeability both in vivo and in vitro. By using pharmacological inhibitors and small interference RNA-based knockdown, we demonstrate an essential role for the PI(3)Kinase-γ/Rac nexus in vGPCR-mediated permeability. This was further accompanied by dramatic remodeling of VE-cadherin-dependent cell-cell junctions. Importantly, this in vitro vGPCR-initiated signaling signature was observed in a large panel of human KS. Altogether, our results support the hypothesis that endothelial vGPCR signaling is co-opted in KS, and unveil new key cellular targets for therapeutic intervention.
Published: 2010

27. Towards Drug Repositioning for Oral Squamous Cell Carcinoma

Author: Eva Maria Galan Moya, Kellen Cristine Tjioe, Julie Gavard, and Denise Tostes Oliveira
Subjects: Drug repositioning, business.industry, Cancer research, Medicine, Radiology, Nuclear Medicine and imaging, Dentistry (miscellaneous), Surgery, Basal cell, Oral Surgery, business, Pathology and Forensic Medicine
Published: 2015
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28. PARP targeting counteracts gliomagenesis through induction of mitotic catastrophe and aggravation of deficiency in homologous recombination in PTEN-mutant glioma

Author: María Isabel Rodríguez, Laura López-Jiménez, Jara Majuelos-Melguizo, Julie Gavard, F. Javier Oliver, José Manuel Rodríguez-Vargas, J. Mariano Ruiz de Almodóvar, Santiago Serrano-Sáenz, and Juan Manuel Martí Martín-Consuegra
Subjects: Genome instability, Adult, Male, PTEN, DNA repair, EGFR, Blotting, Western, Poly (ADP-Ribose) Polymerase-1, Fluorescent Antibody Technique, Mice, Nude, Mitosis, Apoptosis, Poly(ADP-ribose) Polymerase Inhibitors, Real-Time Polymerase Chain Reaction, PARP1, Immunoenzyme Techniques, Mice, Tumor Cells, Cultured, Animals, Humans, EGFR Gene Amplification, RNA, Messenger, Homologous recombination, Mitotic catastrophe, Cell Proliferation, Mice, Inbred BALB C, biology, Brain Neoplasms, Reverse Transcriptase Polymerase Chain Reaction, PTEN Phosphohydrolase, Glioma, genomic instability, Xenograft Model Antitumor Assays, BUBR1, Oncology, PARP inhibitor, Mutation, biology.protein, Cancer research, Poly(ADP-ribose) Polymerases, Glioblastoma, Research Paper
Abstract: Glioblastoma multiforme (GBM) is the most common primary brain tumour in adults and one of the most aggressive cancers. PARP-1 is a nuclear protein involved in multiple facets of DNA repair and transcriptional regulation. In this study we dissected the action of PARP inhibition in different GBM cell lines with either functional or mutated PTEN that confers resistance to diverse therapies. In PTEN mutant cells, PARP inhibition induced a severe genomic instability, exacerbated homologous recombination repair (HR) deficiency and down-regulated the Spindle Assembly Checkpoint (SAC) factor BUBR1, leading to mitotic catastrophe (MC). EGFR gene amplification also represents a signature of genetic abnormality in GBM. To more effectively target GBM cells, co-treatment with a PARP inhibitor and an EGFR blocker, erlotinib, resulted in a strong suppression of ERK1/2 activation and in vivo the combined effect elicited a robust reduction in tumour development. In conclusion, PARP inhibition targets PTEN-deficient GBM cells through accentuation of SAC repression and aggravation of HR deficiency, leading to the induction of genomic instability and eventually deriving to mitotic catastrophe (MC); the inhibition of PARP and co-treatment with an inhibitor of pro-survival pathways strongly retarded in vivo gliomagenesis.

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28 results on '"Julie Gavard"'

1. Abstract P3-11-09: Extracellular vesicle-based biomarker assay for the monitoring of the efficacy of frontline endocrine therapy + CDK4-6 inhibitors in metastatic breast cancer

2. Challenges in glioblastoma research: focus on the tumor microenvironment

3. Antiangiogenic Compound Axitinib Demonstrates Low Toxicity and Antitumoral Effects against Medulloblastoma

4. The von Willebrand Factor stamps Plasmatic Extracellular Vesicles from Glioblastoma Patients

5. Deciphering Tumor Niches: Lessons From Solid and Hematological Malignancies

6. Loss of the Metastasis Suppressor NME1, But Not of Its Highly Related Isoform NME2, Induces a Hybrid Epithelial–Mesenchymal State in Cancer Cells

7. The von Willebrand Factor stamps Plasmatic Extracellular Vesicles from Glioblastoma Patients

8. Author response: Ral GTPases promote breast cancer metastasis by controlling biogenesis and organ targeting of exosomes

9. Vesiclemia: counting on extracellular vesicles for glioblastoma patients

10. Endothelial Cell-Cell Junctions in Tumor Angiogenesis

11. Paracaspase MALT1 regulates glioma cell survival by controlling endo-lysosome homeostasis

12. Inhibition of mTOR in head and neck cancer cells alters endothelial cell morphology in a paracrine fashion

13. Temozolomide affects Extracellular Vesicles Released by Glioblastoma Cells

14. Vaisseaux sanguins et tumeurs ou l’art du dialogue

15. Critical multiple angiogenic factors secreted by glioblastoma stem-like cells underline the need for combinatorial anti-angiogenic therapeutic strategies

16. β-escin selectively targets the glioblastoma-initiating cell population and reduces cell viability

17. Targeted Killing of Cancer Cells in Vivo and in Vitro with EGF-Directed Carbon Nanotube-Based Drug Delivery

18. Extracellular vesicle-transported Semaphorin3A promotes vascular permeability in glioblastoma

19. Luteolin Impacts on the DNA Damage Pathway in Oral Squamous Cell Carcinoma

20. Desert Hedgehog/Patch2 Axis Contributes to Vascular Permeability and Angiogenesis in Glioblastoma

21. L'angiogenèse tumorale Quand l'arbre de vie tourne mal

22. YGLF motif in the Kaposi sarcoma herpes virus G-protein- coupled receptor adjusts NF-kB activation and paracrine actions

23. Vascular Permeability and Drug Delivery in Cancers

24. Differential Proteomic Analysis of Human Glioblastoma and Neural Stem Cells Reveals HDGF as a Novel Angiogenic Secreted Factor

25. Glioblastoma cell-secreted interleukin-8 induces brain endothelial cell permeability via CXCR2

26. Remodeling of VE-cadherin junctions by the human herpes virus 8 G-protein coupled receptor

27. Towards Drug Repositioning for Oral Squamous Cell Carcinoma

28. PARP targeting counteracts gliomagenesis through induction of mitotic catastrophe and aggravation of deficiency in homologous recombination in PTEN-mutant glioma

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28 results on '"Julie Gavard"'

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