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1. In vivo RyR1 reduction in muscle triggers a core-like myopathy

Author

Laurent Pelletier, Anne Petiot, Julie Brocard, Benoit Giannesini, Diane Giovannini, Colline Sanchez, Lauriane Travard, Mathilde Chivet, Mathilde Beaufils, Candice Kutchukian, David Bendahan, Daniel Metzger, Clara Franzini Armstrong, Norma B. Romero, John Rendu, Vincent Jacquemond, Julien Fauré, and Isabelle Marty

Subjects
Ryanodine receptor, Calcium, Skeletal muscle, Excitation–contraction coupling, Congenital myopathies, Central core disease, Neurology. Diseases of the nervous system, RC346-429
Abstract

Abstract Mutations in the RYR1 gene, encoding the skeletal muscle calcium channel RyR1, lead to congenital myopathies, through expression of a channel with abnormal permeability and/or in reduced amount, but the direct functional whole organism consequences of exclusive reduction in RyR1 amount have never been studied. We have developed and characterized a mouse model with inducible muscle specific RYR1 deletion. Tamoxifen-induced recombination in the RYR1 gene at adult age resulted in a progressive reduction in the protein amount reaching a stable level of 50% of the initial amount, and was associated with a progressive muscle weakness and atrophy. Measurement of calcium fluxes in isolated muscle fibers demonstrated a reduction in the amplitude of RyR1-related calcium release mirroring the reduction in the protein amount. Alterations in the muscle structure were observed, with fibers atrophy, abnormal mitochondria distribution and membrane remodeling. An increase in the expression level of many proteins was observed, as well as an inhibition of the autophagy process. This model demonstrates that RyR1 reduction is sufficient to recapitulate most features of Central Core Disease, and accordingly similar alterations were observed in muscle biopsies from Dusty Core Disease patients (a subtype of Central Core Disease), pointing to common pathophysiological mechanisms related to RyR1 reduction.

Published
2020
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2. Evidence for post-translational processing of vascular endothelial (VE)-cadherin in brain tumors: towards a candidate biomarker.

Author

Isabelle Vilgrain, Adama Sidibé, Helena Polena, Francine Cand, Tiphaine Mannic, Mélanie Arboleas, Sandra Boccard, Antoine Baudet, Danielle Gulino-Debrac, Laurence Bouillet, Jean-Louis Quesada, Christophe Mendoza, Jean-François Lebas, Laurent Pelletier, and François Berger

Subjects
Medicine, Science
Abstract

Vessel abnormalities are among the most important features in malignant glioma. Vascular endothelial (VE)-cadherin is of major importance for vascular integrity. Upon cytokine challenge, VE-cadherin structural modifications have been described including tyrosine phosphorylation and cleavage. The goal of this study was to examine whether these events occurred in human glioma vessels. We demonstrated that VE-cadherin is highly expressed in human glioma tissue and tyrosine phosphorylated at site Y(685), a site previously found phosphorylated upon VEGF challenge, via Src activation. In vitro experiments showed that VEGF-induced VE-cadherin phosphorylation, preceded the cleavage of its extracellular adhesive domain (sVE, 90 kDa). Interestingly, metalloproteases (MMPs) secreted by glioma cell lines were responsible for sVE release. Because VEGF and MMPs are important components of tumor microenvironment, we hypothesized that VE-cadherin proteolysis might occur in human brain tumors. Analysis of glioma patient sera prior treatment confirmed the presence of sVE in bloodstream. Furthermore, sVE levels studied in a cohort of 53 glioma patients were significantly predictive of the overall survival at three years (HR 0.13 [0.04; 0.40] p ≤ 0.001), irrespective to histopathological grade of tumors. Altogether, these results suggest that VE-cadherin structural modifications should be examined as candidate biomarkers of tumor vessel abnormalities, with promising applications in oncology.

Published
2013
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3. Early gene expression analysis in 9L orthotopic tumor-bearing rats identifies immune modulation in molecular response to synchrotron microbeam radiation therapy.

Author

Audrey Bouchet, Nathalie Sakakini, Michèle El Atifi, Céline Le Clec'h, Elke Brauer, Anaïck Moisan, Pierre Deman, Pascal Rihet, Géraldine Le Duc, and Laurent Pelletier

Subjects
Medicine, Science
Abstract

Synchrotron Microbeam Radiation Therapy (MRT) relies on the spatial fractionation of the synchrotron photon beam into parallel micro-beams applying several hundred of grays in their paths. Several works have reported the therapeutic interest of the radiotherapy modality at preclinical level, but biological mechanisms responsible for the described efficacy are not fully understood to date. The aim of this study was to identify the early transcriptomic responses of normal brain and glioma tissue in rats after MRT irradiation (400Gy). The transcriptomic analysis of similarly irradiated normal brain and tumor tissues was performed 6 hours after irradiation of 9 L orthotopically tumor-bearing rats. Pangenomic analysis revealed 1012 overexpressed and 497 repressed genes in the irradiated contralateral normal tissue and 344 induced and 210 repressed genes in tumor tissue. These genes were grouped in a total of 135 canonical pathways. More than half were common to both tissues with a predominance for immunity or inflammation (64 and 67% of genes for normal and tumor tissues, respectively). Several pathways involving HMGB1, toll-like receptors, C-type lectins and CD36 may serve as a link between biochemical changes triggered by irradiation and inflammation and immunological challenge. Most immune cell populations were involved: macrophages, dendritic cells, natural killer, T and B lymphocytes. Among them, our results highlighted the involvement of Th17 cell population, recently described in tumor. The immune response was regulated by a large network of mediators comprising growth factors, cytokines, lymphokines. In conclusion, early response to MRT is mainly based on inflammation and immunity which appear therefore as major contributors to MRT efficacy.

Published
2013
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4. Monitoring monoclonal antibody delivery in oncology: the example of bevacizumab.

Author

Guillaume Nugue, Marie Bidart, Marie Arlotto, Mireille Mousseau, François Berger, and Laurent Pelletier

Subjects
Medicine, Science
Abstract

Developing therapeutic monoclonal antibodies paves the way for new strategies in oncology using targeted therapy which should improve specificity. However, due to a lack of biomarkers, a personalized therapy scheme cannot always be applied with monoclonal antibodies. As a consequence, the efficacy or side effects associated with this type of treatment often appear to be sporadic. Bevacizumab is a therapeutic monoclonal antibody targeting Vascular Endothelial Growth Factor (VEGF). It is used to limit tumor vascularization. No prognosis or response biomarker is associated with this antibody, we therefore assessed whether the administration protocol could be a possible cause of heterogeneous responses (or variable efficacy). To do this, we developed a bevacizumab assay with a broad sensitivity range to measure blood bevacizumab concentrations. We then analyzed bevacizumab concentrations in 17 patients throughout the first quarter of treatment. In line with previously published data, average blood concentrations were 88+/-27 mg/L following the first dose administered, and 213+/-105 mg/L after the last (6(th)) dose administered. However, the individual values were scattered, with a mean 4-fold difference between the lowest and the highest concentration for each dose administered. We demonstrated that the bevacizumab administration schedule results in a high inter-individual variability in terms of blood concentrations. Comparison of assay data with clinical data indicates that blood concentrations above the median are associated with side effects, whereas values below the median favor inefficacy. In conclusion, bevacizumab-based therapy could benefit from a personalized administration schedule including follow-up and adjustment of circulating bevacizumab concentrations.

Published
2013
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5. Mild clinical presentation in KLHL40-related nemaline myopathy (NEM 8)

Author

John Rendu, Julien Fauré, Laurent Pelletier, Pierre G. Carlier, Laurent Servais, Norma B. Romero, Andreea Mihaela Seferian, Véronique Forin, Edoardo Malfatti, Teresa Gidaro, Jessica Taytard, E. Gargaun, C Bosson, CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre de référence des maladies rares neuromusculaires, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre de recherche en myologie, Université Pierre et Marie Curie - Paris 6 (UPMC)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Unit of Neuromuscular Morphology [CHU Pitié-Salpêtrière], Institut de Myologie, Université Pierre et Marie Curie - Paris 6 (UPMC)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Association française contre les myopathies (AFM-Téléthon)-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)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-CHU Pitié-Salpêtrière [AP-HP], Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Centre de Recherche Saint-Antoine (UMRS893), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Pneumologie pédiatrique [CHU Trousseau], 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 réhabilitation pédiatrique [CHU Trousseau], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), NMR Laboratory, Université Pierre et Marie Curie - Paris 6 (UPMC)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Association française contre les myopathies (AFM-Téléthon)-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)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), CHU Pitié-Salpêtrière [AP-HP], Institut de Myologie (U153 Inserm - IM), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Centre de référence des maladies rares neuromusculaires [CHU Pitié-Salpétriêre], and HAL-UPMC, Gestionnaire

Subjects
0301 basic medicine, Pathology, medicine.medical_specialty, Muscle Proteins, KLHL40, Biology, medicine.disease_cause, Myopathies, Nemaline, 03 medical and health sciences, symbols.namesake, 0302 clinical medicine, Nemaline myopathy, medicine, Humans, Nemaline bodies, Child, Muscle, Skeletal, Genetics (clinical), Sanger sequencing, Mutation, Muscle biopsy, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, medicine.diagnostic_test, Genetic heterogeneity, medicine.disease, Hypotonia, 3. Good health, 030104 developmental biology, Phenotype, Neurology, Pediatrics, Perinatology and Child Health, symbols, Female, Neurology (clinical), Presentation (obstetrics), medicine.symptom, 030217 neurology & neurosurgery, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract

International audience; Nemaline myopathies are clinically and genetically heterogeneous muscle diseases characterized by the presence of nemaline bodies (rods) in muscle fibers. Mutations in the KLHL40 (kelch-like family member 40) gene (NEM 8) are common cause of severe/lethal nemaline myopathy. We report an 8-year-old girl born to consanguineous Moroccan parents, who presented with hypotonia and poor sucking at birth, delayed motor development, and further mild difficulties in walking and fatigability. A muscle biopsy revealed the presence of nemaline bodies. KLHL40 gene Sanger sequencing disclosed a never before reported pathogenic homozygous mutation which resulted in absent KLHL40 protein expression in the muscle. This further expands the phenotypical spectrum of KLHL40 related nemaline myopathy.

Published
2020
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6. MicroRNA and target protein patterns reveal physiopathological features of glioma subtypes.

Author

Elodie Lages, Audrey Guttin, Michèle El Atifi, Claire Ramus, Hélène Ipas, Isabelle Dupré, Delphine Rolland, Caroline Salon, Catherine Godfraind, Florence deFraipont, Mehdi Dhobb, Laurent Pelletier, Didier Wion, Emmanuel Gay, François Berger, and Jean-Paul Issartel

Subjects
Medicine, Science
Abstract

Gliomas such as oligodendrogliomas (ODG) and glioblastomas (GBM) are brain tumours with different clinical outcomes. Histology-based classification of these tumour types is often difficult. Therefore the first aim of this study was to gain microRNA data that can be used as reliable signatures of oligodendrogliomas and glioblastomas. We investigated the levels of 282 microRNAs using membrane-array hybridisation and real-time PCR in ODG, GBM and control brain tissues. In comparison to these control tissues, 26 deregulated microRNAs were identified in tumours and the tissue levels of seven microRNAs (miR-21, miR-128, miR-132, miR-134, miR-155, miR-210 and miR-409-5p) appropriately discriminated oligodendrogliomas from glioblastomas. Genomic, epigenomic and host gene expression studies were conducted to investigate the mechanisms involved in these deregulations. Another aim of this study was to better understand glioma physiopathology looking for targets of deregulated microRNAs. We discovered that some targets of these microRNAs such as STAT3, PTBP1 or SIRT1 are differentially expressed in gliomas consistent with deregulation of microRNA expression. Moreover, MDH1, the target of several deregulated microRNAs, is repressed in glioblastomas, making an intramitochondrial-NAD reduction mediated by the mitochondrial aspartate-malate shuttle unlikely. Understanding the connections between microRNAs and bioenergetic pathways in gliomas may lead to identification of novel therapeutic targets.

Published
2011
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7. Increased phosphorylation of vimentin in noninfiltrative meningiomas.

Author

Ali Bouamrani, Claire Ramus, Emmanuel Gay, Laurent Pelletier, Myriam Cubizolles, Sabine Brugière, Didier Wion, François Berger, and Jean-Paul Issartel

Subjects
Medicine, Science
Abstract

BackgroundTissue invasion or tissue infiltration are clinical behaviors of a poor-prognosis subset of meningiomas. We carried out proteomic analyses of tissue extracts to discover new markers to accurately distinguish between infiltrative and noninfiltrative meningiomas.Methodology/principal findingsProtein lysates of 64 different tissue samples (including two brain-invasive and 32 infiltrative tumors) were submitted to SELDI-TOF mass spectrometric analysis. Mass profiles were used to build up both unsupervised and supervised hierarchical clustering. One marker was found at high levels in noninvasive and noninfiltrative tumors and appeared to be a discriminative marker for clustering infiltrative and/or invasive meningiomas versus noninvasive meningiomas in two distinct subsets. Sensitivity and specificity were 86.7% and 100%, respectively. This marker was purified and identified as a multiphosphorylated form of vimentin, a cytoskeletal protein expressed in meningiomas.Conclusions/significanceSpecific forms of vimentin can be surrogate molecular indicators of the invasive/infiltrative phenotype in tumors.

Published
2010
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8. Variations in the TRPV1 gene are associated to exertional heat stroke

Author

Fabien van Coppenolle, Julien Fauré, John Rendu, Amandine Chatagnon, Nathalie Roux-Buisson, Dominique Figarella-Branger, Julie Brocard, Amandine Abriat, Laurent Pelletier, Emmanuel Sagui, Isabelle Marty, Sylvie Ducreux, C Bosson, Jacques Brocard, CCSD, Accord Elsevier, CHU Grenoble, Service d'hématologie clinique, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Université Grenoble Alpes (UGA), Groupe d'imagerie neurofonctionnelle (GIN), Institut des Maladies Neurodégénératives [Bordeaux] (IMN), Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS)-Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Centre de Recherches en Oncologie biologique et Oncopharmacologie (CRO2), Aix Marseille Université (AMU)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'Anatomo-Cyto-Pathologie et de NeuroPathologie [Hôpital de la Timone - APHM] (ACPNP), Aix Marseille Université (AMU)- Hôpital de la Timone [CHU - APHM] (TIMONE), Cardiovasculaire, métabolisme, diabétologie et nutrition (CarMeN), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Hospices Civils de Lyon (HCL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), [GIN] Grenoble Institut des Neurosciences (GIN), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes (UGA), Fondation Maladies Rares FONDATION_WES-20150602Institut National de la Sante et de la Recherche Medicale (Inserm) Association Francaise contre les Myopathies (AFM-Telethon), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut des Maladies Neurodégénératives [Bordeaux] (IMN), Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS)-Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS), Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Claude Bernard Lyon 1 (UCBL), and Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hospices Civils de Lyon (HCL)

Subjects
Adult, Male, Candidate gene, Heat Stroke, In silico, [SDV]Life Sciences [q-bio], Mutation, Missense, TRPV1, TRPV Cation Channels, Physical Therapy, Sports Therapy and Rehabilitation, Biology, Bioinformatics, Sudden death, 03 medical and health sciences, Malignant hyperthermia, 0302 clinical medicine, Heat exhaustion, medicine, Humans, Missense mutation, Genetic Predisposition to Disease, Orthopedics and Sports Medicine, 030212 general & internal medicine, Stroke, Gene, Exome sequencing, Whole exome sequencing, Thermogenesis, 030229 sport sciences, medicine.disease, 3. Good health, In vitro contracture test, [SDV] Life Sciences [q-bio], HEK293 Cells, Military Personnel, France
Abstract

International audience; OBJECTIVES: Exertional Heat Stroke (EHS) is one of the top three causes of sudden death in athletes. Extrinsic and intrinsic risk factors have been identified but the genetic causes still remain unclear. Our aim was to identify genes responsible for EHS, which is a necessary step to identify patients at risk and prevent crises. DESIGN: Genetic and functional laboratory studies METHODS: Whole Exome Sequencing (WES) was performed to search for candidate genes in a cohort of 15 soldiers who had a documented EHS episode. In silico and in vitro functional studies were performed to evaluate the effect of mutations identified in the candidate gene TRPV1. RESULTS: WES led to the identification of two missense variations in the TRPV1 gene. These variations were very rare or unreported in control databases and located in critical domains of the protein. In vitro functional studies revealed that both variations induce a strong modification of the channel response to one of its natural agonist, the capsaicin. CONCLUSIONS: We evidenced mutations altering channel properties of the TRPV1 gene and demonstrated that TRPV1, which is involved in thermoregulation and nociception, is a new candidate gene for EHS. Our data provide the bases to explore genetic causes and molecular mechanisms governing the pathophysiology of EHS.

Published
2020
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9. Vasohibins/SVBP are tubulin carboxypeptidases (TCPs) that regulate neuron differentiation

Author

Krzysztof Rogowski, Laurence Lafanechère, Christophe Bosc, Marie-Jo Moutin, Laurent Pelletier, Julien Le Friec, Eric Denarier, Pierre Heemeryck, Christian Delphin, Salahuddin Syed, Benoit Boulan, Frédérique Vossier, Annie Andrieux, Sandrine Humbert, Neri Amara, Yohann Couté, Matthew Bogyo, Juliette van Dijk, Chrystelle Aillaud, Leticia Peris, Laura E. Sanman, Anouk Bosson, Grenoble Institut des Neurosciences (GIN), Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de recherche en Biologie Cellulaire (CRBM), Université Montpellier 2 - Sciences et Techniques (UM2)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Université Montpellier 1 (UM1), Department of Pathology [Stanford], Stanford Medicine, Stanford University-Stanford University, Stanford University, Etude de la dynamique des protéomes (EDyP ), Laboratoire de Biologie à Grande Échelle (BGE - UMR S1038), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Institute for Advanced Biosciences / Institut pour l'Avancée des Biosciences (Grenoble) (IAB), Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Stanford University School of Medicine [CA, USA], Institut de génétique humaine (IGH), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), [GIN] Grenoble Institut des Neurosciences (GIN), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes (UGA), Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), Centre de recherche en Biologie cellulaire de Montpellier (CRBM), Institut de Biosciences et de Biotechnologies de Grenoble (ex-IRTSV) (BIG), Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Recherche Agronomique (INRA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA), Groupe Physiopathologie du Cytosquelette (GPC), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Moutin, Marie-Jo, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), [GIN] Grenoble Institut des Neurosciences, Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM), INSERM U836, équipe 1, Physiopathologie du cytosquelette, Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de recherches de biochimie macromoléculaire (CRBM), Université Montpellier 1 (UM1)-Université Montpellier 2 - Sciences et Techniques (UM2)-IFR122-Centre National de la Recherche Scientifique (CNRS), Institut de Génétique et Développement de Rennes (IGDR), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Department of Pathology, Etude de la dynamique des protéomes (EDyP), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes (UGA)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes (UGA), INSERM U836, équipe 7, Nanomédecine et cerveau, Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble-Institut National de la Santé et de la Recherche Médicale (INSERM)-Service d'oncologie médicale, Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble, Régulations cellulaires et oncogenèse (RCO), and Institut Curie-Centre National de la Recherche Scientifique (CNRS)

Subjects
0301 basic medicine, Gene knockdown, Multidisciplinary, [SDV]Life Sciences [q-bio], [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, [SDV.NEU.NB] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Biology, Carboxypeptidase, Carboxypeptidase activity, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, Tubulin, Biochemistry, Microtubule, Detyrosination, Neuron differentiation, biology.protein, Tyrosine, 030217 neurology & neurosurgery, ComputingMilieux_MISCELLANEOUS
Abstract

Tubulin carboxypeptidase identity revealed Enzymes of the α-tubulin detyrosination/tyrosination cycle create landmarks on microtubules that are essential for their multiple cellular functions and are altered in disease. Tubulin carboxypeptidases (TCPs) responsible for detyrosination have remained elusive for 40 years (see the Perspective by Akhmanova and Maiato). Aillaud et al. identified vasohibins as enzymes that perform the TCP function and found that their small interacting partner SBVP was essential for their activity. Vasohibin/SVBP complexes were involved in neuron polarization and brain cortex development. The authors also developed an inhibitor targeting this family of enzymes. Using a completely different strategy, Nieuwenhuis et al. also showed that vasohibins can remove the C-terminal tyrosine of α-tubulin. Science , this issue p. 1448 , p. 1453 ; see also p. 1381

Published
2017
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10. Characterization of the 9L gliosarcoma implanted in the Fischer rat: an orthotopic model for a grade IV brain tumor

Author

Céline Le Clec'h, Laurent Pelletier, Audrey Bouchet, Marie Bidart, Pierrick Regnard, Jean A. Laissue, Raphaël Serduc, Sandrine Dufort, Benjamin Lemasson, Imen Miladi, Enam A. Khalil, Charles Coutton, Géraldine Le Duc, European Synchrotron Radiation Facility (ESRF), Grenoble Institut des Neurosciences (GIN), Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Grenoble, Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble, AGeing and IMagery (AGIM), Centre National de la Recherche Scientifique (CNRS)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Joseph Fourier - Grenoble 1 (UJF)-Université Pierre Mendès France - Grenoble 2 (UPMF), Institut d'oncologie/développement Albert Bonniot de Grenoble (INSERM U823), Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM), Nano-H S.A.S, LyonBioPôle, Institute of Anatomy, University of Bern, INCA Bioresys 200187, European Synchrotron Radiation Facility ( ESRF ), Grenoble Institut des Neurosciences ( GIN ), Université Joseph Fourier - Grenoble 1 ( UJF ) -CHU Grenoble-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Université Joseph Fourier - Grenoble 1 ( UJF ) -CHU Grenoble, Laboratoire de Physico-Chimie des Matériaux Luminescents ( LPCML ), Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique ( CNRS ), AGeing and IMagery ( AGIM ), Université Pierre Mendès France - Grenoble 2 ( UPMF ) -Université Joseph Fourier - Grenoble 1 ( UJF ) -École pratique des hautes études ( EPHE ) -Centre National de la Recherche Scientifique ( CNRS ), Institut d'oncologie/développement Albert Bonniot de Grenoble ( INSERM U823 ), Université Joseph Fourier - Grenoble 1 ( UJF ) -CHU Grenoble-EFS-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Université Pierre Mendès France - Grenoble 2 (UPMF)-Université Joseph Fourier - Grenoble 1 (UJF)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS), and Issartel, Jean-Paul

Subjects
Pathology, medicine.medical_specialty, Proliferative index, medicine.medical_treatment, Brain tumor, Gliosarcoma, 030218 nuclear medicine & medical imaging, 03 medical and health sciences, 0302 clinical medicine, Glioma, medicine, Animals, Humans, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Cytogenetic, Cell Proliferation, medicine.diagnostic_test, Neovascularization, Pathologic, Radiotherapy, business.industry, Brain Neoplasms, Infiltration, Histology, Magnetic resonance imaging, General Medicine, Neoplasms, Experimental, medicine.disease, Rats, Inbred F344, Hypervascularization, 3. Good health, Rats, Radiation therapy, Disease Models, Animal, 030220 oncology & carcinogenesis, [ SDV.NEU ] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Immunohistochemistry, Rat, 9L, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Neoplasm Grading, business, Immunostaining, Neoplasm Transplantation
Abstract

International audience; Among rodent models for brain tumors, the 9L gliosarcoma is one of the most widely used. Our 9L-European Synchrotron Radiation Facility (ESRF) model was developed from cells acquired at the Brookhaven National Laboratory (NY, USA) in 1997 and implanted in the right caudate nucleus of syngeneic Fisher rats. It has been largely used by the user community of the ESRF during the last decade, for imaging, radiotherapy, and chemotherapy, including innovative treatments based on particular irradiation techniques and/or use of new drugs. This work presents a detailed study of its characteristics, assessed by magnetic resonance imaging (MRI), histology, immunohistochemistry, and cytogenetic analysis. The data used for this work were from rats sampled in six experiments carried out over a 3-year period in our lab (total number of rats = 142). The 9L-ESRF tumors were induced by a stereotactic inoculation of 10(4) 9L cells in the right caudate nucleus of the brain. The assessment of vascular parameters was performed by MRI (blood volume fraction and vascular size index) and by immunostaining of vessels (rat endothelial cell antigen-1 and type IV collagen). Immunohistochemistry and regular histology were used to describe features such as tumor cell infiltration, necrosis area, nuclear pleomorphism, cellularity, mitotic characteristics, leukocytic infiltration, proliferation, and inflammation. Moreover, for each of the six experiments, the survival of the animals was assessed and related to the tumor growth observed by MRI or histology. Additionally, the cytogenetic status of the 9L cells used at ESRF lab was investigated by comparative genomics hybridization analysis. Finally, the response of the 9L-ESRF tumor to radiotherapy was estimated by plotting the survival curves after irradiation. The median survival time of 9L-ESRF tumor-bearing rats was highly reproducible (19-20 days). The 9L-ESRF tumors presented a quasi-exponential growth, were highly vascularized with a high cellular density and a high proliferative index, accompanied by signs of inflammatory responses. We also report an infiltrative pattern which is poorly observed on conventional 9 L tumor. The 9L-ESRF cells presented some cytogenetic specificities such as altered regions including CDK4, CDKN2A, CDKN2B, and MDM2 genes. Finally, the lifespan of 9L-ESRF tumor-bearing rats was enhanced up to 28, 35, and 45 days for single doses of 10, 20, and 2 × 20 Gy, respectively. First, this report describes an animal model that is used worldwide. Second, we describe few features typical of our model if compared to other 9L models worldwide. Altogether, the 9L-ESRF tumor model presents characteristics close to the human high-grade gliomas such as high proliferative capability, high vascularization and a high infiltrative pattern. Its response to radiotherapy demonstrates its potential as a tool for innovative radiotherapy protocols.

Published
2014
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12. Evidence for post-translational processing of vascular endothelial (VE)-cadherin in brain tumors: towards a candidate biomarker

Author

Tiphaine Mannic, Francine Cand, Laurent Pelletier, Mélanie Arboleas, Jean-Louis Quesada, Jean-Francois LeBas, Christophe Mendoza, Laurence Bouillet, Isabelle Vilgrain, Danielle Gulino-Debrac, François Berger, Sandra Boccard, Adama Sidibé, Helena Polena, and Antoine Baudet

Subjects
Adult, Male, Pathology, medicine.medical_specialty, Endothelium, lcsh:Medicine, chemistry.chemical_compound, Young Adult, Antigens, CD, Glioma, medicine, Biomarkers, Tumor, Human Umbilical Vein Endothelial Cells, Tumor Microenvironment, Humans, Phosphorylation, lcsh:Science, Aged, Tumor microenvironment, Multidisciplinary, Chemistry, Cadherin, Brain Neoplasms, lcsh:R, Endothelial Cells, Tyrosine phosphorylation, Middle Aged, medicine.disease, Cadherins, medicine.anatomical_structure, Female, lcsh:Q, Endothelium, Vascular, VE-cadherin, Proto-oncogene tyrosine-protein kinase Src, Research Article
Abstract

Vessel abnormalities are among the most important features in malignant glioma. Vascular endothelial (VE)-cadherin is of major importance for vascular integrity. Upon cytokine challenge, VE-cadherin structural modifications have been described including tyrosine phosphorylation and cleavage. The goal of this study was to examine whether these events occurred in human glioma vessels. We demonstrated that VE-cadherin is highly expressed in human glioma tissue and tyrosine phosphorylated at site Y(685), a site previously found phosphorylated upon VEGF challenge, via Src activation. In vitro experiments showed that VEGF-induced VE-cadherin phosphorylation, preceded the cleavage of its extracellular adhesive domain (sVE, 90 kDa). Interestingly, metalloproteases (MMPs) secreted by glioma cell lines were responsible for sVE release. Because VEGF and MMPs are important components of tumor microenvironment, we hypothesized that VE-cadherin proteolysis might occur in human brain tumors. Analysis of glioma patient sera prior treatment confirmed the presence of sVE in bloodstream. Furthermore, sVE levels studied in a cohort of 53 glioma patients were significantly predictive of the overall survival at three years (HR 0.13 [0.04; 0.40] p ≤ 0.001), irrespective to histopathological grade of tumors. Altogether, these results suggest that VE-cadherin structural modifications should be examined as candidate biomarkers of tumor vessel abnormalities, with promising applications in oncology.

Published
2013

13. MicroRNA and target protein patterns reveal physiopathological features of glioma subtypes

Author

Hélène Ipas, Jean-Paul Issartel, Claire Ramus, Laurent Pelletier, Mehdi Dhobb, Didier Wion, Florence deFraipont, François Berger, Isabelle Dupré, Elodie Lages, Catherine Godfraind, Michèle El Atifi, Caroline Salon, Delphine Rolland, Audrey Guttin, Inserm U836, équipe 7, Nanomédecine et cerveau, Grenoble Institut des Neurosciences (GIN), Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM), INSERM U836, équipe 7, Nanomédecine et cerveau, Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Clinical Transcriptomics and Proteomics Platform, CHU Grenoble-CHU Grenoble, CHU Grenoble-CHU Grenoble-Laboratoire d'Hématologie Cellulaire et Moléculaire, CHU Grenoble, Service de Pathologie, Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble, Laboratoire de Neuropathologie, Université Catholique de Louvain = Catholic University of Louvain (UCL)-Clinique Saint-Luc, Institut d'oncologie/développement Albert Bonniot de Grenoble (INSERM U823), Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Neurochirurgie, CHU Grenoble-Hôpital Michallon, This study was supported by grants from the Ligue contre le Cancer (comité Isère and Ligue Nationale) (http://www.ligue-cancer.net/), the Région Rhône-Alpes(http://www.rhonealpes.fr/), the Lyon, Auvergne, Rhône-Alpes Cancéropole (http://www.canceropole-clara.com/) and the Institut National du Cancer (http://www.e-cancer.fr/)., Issartel, Jean-Paul, and UCL - (SLuc) Service d'anatomie pathologique

Subjects
MESH: Cell Hypoxia, lcsh:Medicine, Bioinformatics, Polymerase Chain Reaction, Heterogeneous-Nuclear Ribonucleoproteins, MESH: Glioma, 0302 clinical medicine, Molecular cell biology, RNA interference, MESH: DNA Methylation, Sirtuin 1, Gene expression, MESH: Sirtuin 1, MESH: CpG Islands, lcsh:Science, Neurological Tumors, Epigenomics, 0303 health sciences, Multidisciplinary, MESH: STAT3 Transcription Factor, PTBP1, Glioma, Cell Hypoxia, CpG site, Oncology, 030220 oncology & carcinogenesis, DNA methylation, Medicine, MESH: Polypyrimidine Tract-Binding Protein, Research Article, Polypyrimidine Tract-Binding Protein, STAT3 Transcription Factor, MESH: Cell Line, Tumor, Oligodendroglioma, Blotting, Western, [SDV.CAN]Life Sciences [q-bio]/Cancer, Biology, In Vitro Techniques, 03 medical and health sciences, [SDV.CAN] Life Sciences [q-bio]/Cancer, Cell Line, Tumor, microRNA, medicine, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Humans, MESH: Blotting, Western, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, neoplasms, 030304 developmental biology, MESH: Heterogeneous-Nuclear Ribonucleoproteins, MESH: Humans, lcsh:R, Cancers and Neoplasms, MESH: Polymerase Chain Reaction, DNA Methylation, medicine.disease, nervous system diseases, MicroRNAs, Cancer research, CpG Islands, lcsh:Q, MESH: MicroRNAs, Glioblastoma Multiforme
Abstract

International audience; Gliomas such as oligodendrogliomas (ODG) and glioblastomas (GBM) are brain tumours with different clinical outcomes. Histology-based classification of these tumour types is often difficult. Therefore the first aim of this study was to gain microRNA data that can be used as reliable signatures of oligodendrogliomas and glioblastomas. We investigated the levels of 282 microRNAs using membrane-array hybridisation and real-time PCR in ODG, GBM and control brain tissues. In comparison to these control tissues, 26 deregulated microRNAs were identified in tumours and the tissue levels of seven microRNAs (miR-21, miR-128, miR-132, miR-134, miR-155, miR-210 and miR-409-5p) appropriately discriminated oligodendrogliomas from glioblastomas. Genomic, epigenomic and host gene expression studies were conducted to investigate the mechanisms involved in these deregulations. Another aim of this study was to better understand glioma physiopathology looking for targets of deregulated microRNAs. We discovered that some targets of these microRNAs such as STAT3, PTBP1 or SIRT1 are differentially expressed in gliomas consistent with deregulation of microRNA expression. Moreover, MDH1, the target of several deregulated microRNAs, is repressed in glioblastomas, making an intramitochondrial-NAD reduction mediated by the mitochondrial aspartate-malate shuttle unlikely. Understanding the connections between microRNAs and bioenergetic pathways in gliomas may lead to identification of novel therapeutic targets.

Published
2011
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14. RNA mutagenesis and sporadic prion diseases

Author

Emmanuel Garcion, Laurent Pelletier, Didier Wion, Bradley Wallace, Ingénierie de la vectorisation particulaire, Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Neurosciences précliniques, Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM), and wion, didier

Subjects
Statistics and Probability, PrPSc Proteins, Prions, animal diseases, Population, Mutagenesis (molecular biology technique), Biology, medicine.disease_cause, General Biochemistry, Genetics and Molecular Biology, Prion Diseases, 03 medical and health sciences, chemistry.chemical_compound, Germline mutation, medicine, Animals, Humans, education, 030304 developmental biology, Genetics, 0303 health sciences, education.field_of_study, Messenger RNA, Mutation, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, General Immunology and Microbiology, Applied Mathematics, 030302 biochemistry & molecular biology, RNA, Translation (biology), General Medicine, Virology, 3. Good health, nervous system diseases, chemistry, Mutagenesis, Modeling and Simulation, Prion, RNA Editing, General Agricultural and Biological Sciences, DNA, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract

International audience; The extremely low incidence of sporadic prion diseases suggests that they may arise as a rare stochastic event in otherwise healthy animals or humans. Current hypotheses for sporadic prion disease include horizontal transmission, spontaneous conversion of Prp C into Prp Sc , and somatic mutation of the Prp gene. Here, we suggest RNA mutation as a possible initial event in the etiology of sporadic prion disease. The proposed model is based on (i) the fact that in Prp-expressing cells, mutations are statistically more likely to occur in the Prp mRNA population than in the corresponding two copies of the Prp gene, and (ii) the absence of RNA repair mechanisms analagous to those found for DNA mismatch correction resulting in a relatively higher rate of RNA mutations. Here, we suggest that translation of mutated Prp mRNA could lead to the synthesis of transient Prp Sc which results in the conversion of Prp C into Prp Sc and the propagation of a disease-associated isoform. This model points to RNA mutation as a possible mechanism for the generation of sporadic prion diseases and other pathological disorders in which infectious proteins other than Prp Sc might be implicated.

Published
2004
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16. Je découvre.

Author

ST-LAURENT PELLETIER, RAPHAËLE

Published
2018

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