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28 results on '"Thierry, Virolle"'

1. Glioblastoma cell motility depends on enhanced oxidative stress coupled with mobilization of a sulfurtransferase

Author

Mirca S. Saurty-Seerunghen, Thomas Daubon, Léa Bellenger, Virgile Delaunay, Gloria Castro, Joris Guyon, Ahmed Rezk, Sylvie Fabrega, Ahmed Idbaih, Fabien Almairac, Fanny Burel-Vandenbos, Laurent Turchi, Eric Duplus, Thierry Virolle, Jean-Michel Peyrin, Christophe Antoniewski, Hervé Chneiweiss, Elias A. El-Habr, and Marie-Pierre Junier

Subjects
Cytology, QH573-671
Abstract

Abstract Cell motility is critical for tumor malignancy. Metabolism being an obligatory step in shaping cell behavior, we looked for metabolic weaknesses shared by motile cells across the diverse genetic contexts of patients’ glioblastoma. Computational analyses of single-cell transcriptomes from thirty patients’ tumors isolated cells with high motile potential and highlighted their metabolic specificities. These cells were characterized by enhanced mitochondrial load and oxidative stress coupled with mobilization of the cysteine metabolism enzyme 3-Mercaptopyruvate sulfurtransferase (MPST). Functional assays with patients’ tumor-derived cells and -tissue organoids, and genetic and pharmacological manipulations confirmed that the cells depend on enhanced ROS production and MPST activity for their motility. MPST action involved protection of protein cysteine residues from damaging hyperoxidation. Its knockdown translated in reduced tumor burden, and a robust increase in mice survival. Starting from cell-by-cell analyses of the patients’ tumors, our work unravels metabolic dependencies of cell malignancy maintained across heterogeneous genomic landscapes.

Published
2022
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2. SETMAR Shorter Isoform: A New Prognostic Factor in Glioblastoma

Author

Oriane Lié, Thierry Virolle, Mathieu Gabut, Claude Pasquier, Ilyess Zemmoura, and Corinne Augé-Gouillou

Subjects
glioblastoma, GBM, SETMAR, prognostic factor, patient cohorts study, survival, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Recent evidence suggests that the chimeric protein SETMAR is a factor of interest in cancer, especially in glioblastoma. However, little is known about the expression of this protein in glioblastoma tissues, and no study has been done to assess if SETMAR could be a prognostic and/or diagnostic marker of glioblastoma. We analyzed protein extracts of 47 glioblastoma samples coming from a local and a national cohort of patients. From the local cohort, we obtained localized biopsies from the central necrosis area, the tumor, and the perilesional brain. From the French Glioblastoma Biobank (FGB), we obtained three types of samples: from the same tumors before and after treatment, from long survivors, and from very short survivors. We studied the correlations between SETMAR amounts, clinical profiles of patients and other associated proteins (PTN, snRNP70 and OLIG2). In glioblastoma tissues, the shorter isoform of SETMAR (S-SETMAR) was predominant over the full-length isoform (FL-SETMAR), and the expression of both SETMAR variants was higher in the tumor compared to the perilesional tissues. Data from the FGB showed that SETMAR amounts were not different between the initial tumors and tumor relapses after treatment. These data also showed a trend toward higher amounts of S-SETMAR in long survivors. In localized biopsies, we found a positive correlation between good prognosis and large amounts of S-SETMAR in the perilesional area. This is the main result presented here: survival in Glioblastoma is correlated with amounts of S-SETMAR in perilesional brain, which should be considered as a new relevant prognosis marker.

Published
2022
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3. Mitochondria Transfer from Mesenchymal Stem Cells Confers Chemoresistance to Glioblastoma Stem Cells through Metabolic Rewiring

Author

Jean Nakhle, Khattar Khattar, Tülin Özkan, Adel Boughlita, Daouda Abba Moussa, Amelie Darlix, Frédérique Lorcy, Valérie RIGAU, Luc BAUCHET, Sabine Gerbal-Chaloin, Martine Daujat-Chavanieu, Floriant Bellvert, Laurent Turchi, Thierry Virolle, Jean-Philippe Hugnot, Nicolas Buisine, Mireille Galloni, Valerie Dardalhon, Anne-Marie Rodriguez, Marie-Luce Vignais, 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), Institut de Génétique Moléculaire de Montpellier (IGMM), Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), Geroscience and rejuvenation research center (RESTORE), Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), CHU Montpellier, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Ankara University School of Medicine [Turkey], Université de Montpellier (UM), Institut du Cancer de Montpellier (ICM), Hôpital Gui de Chauliac [CHU Montpellier], Neurochirurgie [Hôpital Gui de Chauliac], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Gui de Chauliac [CHU Montpellier], Toulouse Biotechnology Institute (TBI), Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), Institut National des Sciences Appliquées (INSA)-Université de Toulouse (UT)-Institut National des Sciences Appliquées (INSA)-Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), MetaToul FluxoMet (TBI-MetaToul), MetaboHUB-MetaToul, MetaboHUB-Génopole Toulouse Midi-Pyrénées [Auzeville] (GENOTOUL), Université de Toulouse (UT)-Université de Toulouse (UT)-Ecole Nationale Vétérinaire de Toulouse (ENVT), Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-MetaboHUB-Génopole Toulouse Midi-Pyrénées [Auzeville] (GENOTOUL), Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Toulouse Biotechnology Institute (TBI), Institut National des Sciences Appliquées (INSA)-Université de Toulouse (UT)-Institut National des Sciences Appliquées (INSA)-Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), Institut National des Sciences Appliquées (INSA)-Université de Toulouse (UT)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Institut de Biologie Valrose (IBV), 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), Physiologie moléculaire et adaptation (PhyMA), Muséum national d'Histoire naturelle (MNHN)-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), Adaptation Biologique et Vieillissement = Biological Adaptation and Ageing (B2A), 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), ANR-11-INBS-0010,METABOHUB,Développement d'une infrastructure française distribuée pour la métabolomique dédiée à l'innovation(2011), Institut de recherche en biothérapie, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Neuroradiologie [Hôpital Gui de Chauliac], and Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)

Subjects
[SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, [SDV.BC.IC]Life Sciences [q-bio]/Cellular Biology/Cell Behavior [q-bio.CB], [SDV.CAN]Life Sciences [q-bio]/Cancer, [SDV.BC]Life Sciences [q-bio]/Cellular Biology
Abstract

International audience; Glioblastomas (GBM) are heterogeneous tumors with high metabolic plasticity. Their poor prognosis is linked to the presence of glioblastoma stem cells (GSC), which support resistance to therapy, notably to temozolomide (TMZ). Mesenchymal stem cells (MSC) recruitment to GBM contributes to GSC chemoresistance, by mechanisms still poorly understood. Here, we provide evidence that MSCs transfer mitochondria to GSCs through tunneling nanotubes, which enhances GSCs resistance to TMZ. More precisely, our metabolomics analyses reveal that MSC mitochondria induce GSCs metabolic reprograming, with a nutrient shift from glucose to glutamine, a rewiring of the tricarboxylic acid cycle from glutaminolysis to reductive carboxylation and increase in orotate turnover as well as in pyrimidine and purine synthesis. Metabolomics analysis of GBM patient tissues at relapse after TMZ treatment documents increased concentrations of AMP, CMP, GMP, and UMP nucleotides and thus corroborate our in vitro analyses. Finally, we provide a mechanism whereby mitochondrial transfer from MSCs to GSCs contributes to GBM resistance to TMZ therapy, by demonstrating that inhibition of orotate production by Brequinar (BRQ) restores TMZ sensitivity in GSCs with acquired mitochondria. Altogether, these results identify a mechanism for GBM resistance to TMZ and reveal a metabolic dependency of chemoresistant GBM following the acquisition of exogenous mitochondria, which opens therapeutic perspectives based on synthetic lethality between TMZ and BRQ.Significance: Mitochondria acquired from MSCs enhance the chemoresistance of GBMs. The discovery that they also generate metabolic vulnerability in GSCs paves the way for novel therapeutic approaches.

Published
2023
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4. Figure S4 from Mitochondria transfer from mesenchymal stem cells confers chemoresistance to Glioblastoma stem cells through metabolic rewiring

Author

Marie-Luce Vignais, Anne-Marie Rodriguez, Valerie Dardalhon, Mireille Galloni, Nicolas Buisine, Jean-Philippe Hugnot, Thierry Virolle, Laurent Turchi, Floriant Bellvert, Martine Daujat-Chavanieu, Sabine Gerbal-Chaloin, Luc BAUCHET, Valérie RIGAU, Frédérique Lorcy, Amelie Darlix, Daouda Abba Moussa, Adel Boughlita, Tülin Özkan, Khattar Khattar, and Jean Nakhle

Abstract

Metabolites produced by GSCs following MSC mitochondria acquisition and TMZ treatment

Published
2023
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5. Supplementary Materials and Methods from Mitochondria transfer from mesenchymal stem cells confers chemoresistance to Glioblastoma stem cells through metabolic rewiring

Author

Marie-Luce Vignais, Anne-Marie Rodriguez, Valerie Dardalhon, Mireille Galloni, Nicolas Buisine, Jean-Philippe Hugnot, Thierry Virolle, Laurent Turchi, Floriant Bellvert, Martine Daujat-Chavanieu, Sabine Gerbal-Chaloin, Luc BAUCHET, Valérie RIGAU, Frédérique Lorcy, Amelie Darlix, Daouda Abba Moussa, Adel Boughlita, Tülin Özkan, Khattar Khattar, and Jean Nakhle

Abstract

TMZ dose-response assay Caspase-GloⓇ 3/7 assay Cytotox assay Extracellular Flux Assays Cell Proliferation Western Blot Flow Cytometry Metabolite usage Mitoplates Mass Spectrometry Quantification 13C stable isotope tracing experiments Preparation and quantification of MSC mtDNA in GSCs Imaging

Published
2023
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6. Video 1 from Mitochondria transfer from mesenchymal stem cells confers chemoresistance to Glioblastoma stem cells through metabolic rewiring

Author

Marie-Luce Vignais, Anne-Marie Rodriguez, Valerie Dardalhon, Mireille Galloni, Nicolas Buisine, Jean-Philippe Hugnot, Thierry Virolle, Laurent Turchi, Floriant Bellvert, Martine Daujat-Chavanieu, Sabine Gerbal-Chaloin, Luc BAUCHET, Valérie RIGAU, Frédérique Lorcy, Amelie Darlix, Daouda Abba Moussa, Adel Boughlita, Tülin Özkan, Khattar Khattar, and Jean Nakhle

Abstract

Cocultures of red MitoTracker-labeled MSCs and green CellTracker-labeled GSCs

Published
2023
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7. Data from Mitochondria transfer from mesenchymal stem cells confers chemoresistance to Glioblastoma stem cells through metabolic rewiring

Author

Marie-Luce Vignais, Anne-Marie Rodriguez, Valerie Dardalhon, Mireille Galloni, Nicolas Buisine, Jean-Philippe Hugnot, Thierry Virolle, Laurent Turchi, Floriant Bellvert, Martine Daujat-Chavanieu, Sabine Gerbal-Chaloin, Luc BAUCHET, Valérie RIGAU, Frédérique Lorcy, Amelie Darlix, Daouda Abba Moussa, Adel Boughlita, Tülin Özkan, Khattar Khattar, and Jean Nakhle

Abstract

Glioblastomas (GBM) are heterogeneous tumors with high metabolic plasticity. Their poor prognosis is linked to the presence of glioblastoma stem cells (GSCs), which support resistance to therapy, notably to temozolomide (TMZ). Mesenchymal stem cells (MSCs) recruitment to GBM contributes to GSC chemoresistance, by mechanisms still poorly understood. Here, we provide evidence that MSCs transfer mitochondria to GSCs through tunneling nanotubes, which enhances GSCs resistance to TMZ. More precisely, our metabolomics analyses reveal that MSC mitochondria induce GSCs metabolic reprograming, with a nutrient shift from glucose to glutamine, a rewiring of the TCA cycle from glutaminolysis to reductive carboxylation and increase in orotate turnover as well as in pyrimidine and purine synthesis. Metabolomics analysis of GBM patient tissues at relapse after TMZ treatment documents increased concentrations of AMP, CMP, GMP and UMP nucleotides and thus corroborate our in vitro analyses. Finally, we provide a mechanism whereby mitochondrial transfer from MSCs to GSCs contributes to GBM resistance to TMZ therapy, by demonstrating that inhibition of orotate production by Brequinar (BRQ) restores TMZ sensitivity in GSCs with acquired mitochondria. Altogether, these results identify a mechanism for GBM resistance to TMZ and reveal a metabolic dependency of chemoresistant GBM following the acquisition of exogenous mitochondria, which opens therapeutic perspectives based on synthetic lethality between TMZ and BRQ.

Published
2023
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8. Data from ERK-Mediated Loss of miR-199a-3p and Induction of EGR1 Act as a 'Toggle Switch' of GBM Cell Dedifferentiation into NANOG- and OCT4-Positive Cells

Author

Thierry Virolle, Fanny Burel-Vandenbos, Patrick Verrando, Marie-Pierre Junier, Herve Chneiweiss, Philippe Paquis, Denys Fontaine, Laurence Bianchini, Beatrice Polo, Elisabet Gjernes, Sarah Elkeurti, David Nicolas Debruyne, Nathalie Sakakini, Laurent Turchi, and Fabien Almairac

Abstract

There is great interest in understanding how the cancer stem cell population may be maintained in solid tumors. Here, we show that tumor cells exhibiting stem-like properties and expression of pluripotency markers NANOG and OCT4 can arise from original differentiated tumor cells freshly isolated from human glioblastomas (GBM) and that have never known any serum culture conditions. Induction of EGR1 by EGFR/ERK signaling promoted cell conversion from a less aggressive, more differentiated cellular state to a self-renewing and strongly tumorigenic state, expressing NANOG and OCT4. Expression of these pluripotency markers occurred before the cells re-entered the cell cycle, demonstrating their capacity to change and dedifferentiate without any cell divisions. In differentiated GBM cells, ERK-mediated repression of miR-199a-3p induced EGR1 protein expression and triggered dedifferentiation. Overall, this signaling pathway constitutes an ERK-mediated "toggle switch" that promotes pluripotency marker expression and stem-like features in GBM cells.Significance:This study defines an ERK-mediated molecular mechanism of dedifferentiation of GBM cells into a stem-like state, expressing markers of pluripotency.See related commentary by Koncar and Agnihotri, p. 3195

Published
2023
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9. figure legends and tables from ERK-Mediated Loss of miR-199a-3p and Induction of EGR1 Act as a 'Toggle Switch' of GBM Cell Dedifferentiation into NANOG- and OCT4-Positive Cells

Author

Thierry Virolle, Fanny Burel-Vandenbos, Patrick Verrando, Marie-Pierre Junier, Herve Chneiweiss, Philippe Paquis, Denys Fontaine, Laurence Bianchini, Beatrice Polo, Elisabet Gjernes, Sarah Elkeurti, David Nicolas Debruyne, Nathalie Sakakini, Laurent Turchi, and Fabien Almairac

Abstract

this text corresponds to the legends of supplemental tables 1 to 3 and supplemental figures 1 to 14

Published
2023
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10. Supplementary Data from ERK-Mediated Loss of miR-199a-3p and Induction of EGR1 Act as a 'Toggle Switch' of GBM Cell Dedifferentiation into NANOG- and OCT4-Positive Cells

Author

Thierry Virolle, Fanny Burel-Vandenbos, Patrick Verrando, Marie-Pierre Junier, Herve Chneiweiss, Philippe Paquis, Denys Fontaine, Laurence Bianchini, Beatrice Polo, Elisabet Gjernes, Sarah Elkeurti, David Nicolas Debruyne, Nathalie Sakakini, Laurent Turchi, and Fabien Almairac

Abstract

The supplemental figure 12 describes EGR1 expression during cell dedifferentiation. The supplemental figure 13 descries miR-199a-3p conserved sites in EGR1 3'UTR. The supplemental figure 14 describes the effects of shEGR1 and synthetic miR-199a-3p on EGR1 and miR-199a-3p expression and the consequence on NANOG expression.

Published
2023
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11. Supplementary tables S1-S3 from ERK-Mediated Loss of miR-199a-3p and Induction of EGR1 Act as a 'Toggle Switch' of GBM Cell Dedifferentiation into NANOG- and OCT4-Positive Cells

Author

Thierry Virolle, Fanny Burel-Vandenbos, Patrick Verrando, Marie-Pierre Junier, Herve Chneiweiss, Philippe Paquis, Denys Fontaine, Laurence Bianchini, Beatrice Polo, Elisabet Gjernes, Sarah Elkeurti, David Nicolas Debruyne, Nathalie Sakakini, Laurent Turchi, and Fabien Almairac

Abstract

tables describing OCT4 and NANOG positive cells (sup table S1); tables describing gene clustering and GEO (sup tables S2 and S3)

Published
2023
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12. 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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13. [18F] FDOPA standardized uptake values of brain tumors are not exclusively dependent on LAT1 expression.

Author

Bérengère Dadone-Montaudié, Damien Ambrosetti, Maxime Dufour, Jacques Darcourt, Fabien Almairac, John Coyne, Thierry Virolle, Olivier Humbert, and Fanny Burel-Vandenbos

Subjects
Medicine, Science
Abstract

[18F]-FDOPA is a labeled amino acid (AA) analog used for positron emission tomography (PET) which is gaining increasing interest in the evaluation of brain tumors (BT). The AA-transporter LAT1 has been shown to be involved in [18F]-FDOPA uptake. The aim of this study was to determine whether the [18F]-FDOPA uptake was correlated with level of LAT1 expression in BT. Twenty-eight BT (including 19 gliomas and 9 metastases) were investigated by [18F]-FDOPA-PET prior to surgery and by anti-LAT1 immunohistochemistry on surgical specimens. The quantitative [18F]-FDOPA measured parameters were SUVmax, SUVmean and SUVpeak. LAT1 expression was quantified using a score (0 to 400). A significant [18F]-FDOPA uptake was associated with a LAT1 score ≥ 100 (p = 0.02) but there was no linear correlation between intensity of [18F]-FDOPA uptake and score of LAT1 expression whatever the parameters considered. LAT1 expression alone is not sufficient to explain variation of intensity of [18F]-FDOPA uptake in BT.

Published
2017
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14. Human glioblastoma cell motility depends on the activity of the cysteine metabolism enzyme 3-Mercaptopyruvate sulfurtransferase

Author

Mirca S. Saurty-Seerunghen, Thomas Daubon, Léa Bellenger, Virgile Delaunay, Gloria Castro, Joris Guyon, Ahmed Rezk, Sylvie Fabrega, Ahmed Idbaih, Fabien Almairac, Fanny Burel-Vandenbos, Laurent Turchi, Thierry Virolle, Jean-Michel Peyrin, Christophe Antoniewski, Hervé Chneiweiss, Elias A. El-Habr, and Marie-Pierre Junier

Abstract

Cancer cells in similar functional states are found in all glioblastoma, despite the genomic heterogeneity observed between and within these brain tumors. Metabolism being downstream of all signaling pathways regulating cell behaviors, we looked for metabolic weaknesses in link with motility, a key functional state for glioblastoma aggressiveness. A signature-driven data reduction approach highlighted motile cells present in thirty tumors from four independent single-cell transcriptomic datasets. Analyses integrating trajectory modeling disclosed, as characteristic of motile cells, enhanced oxidative stress coupled with mobilization of the cysteine metabolism enzyme 3-Mercaptopyruvate sulfurtransferase (MPST). The soundness of this prediction was verified using migration and invasion assays with patient-derived cells and tissue organoids. Pharmacological and genetic manipulations showed that enhanced ROS production and MPST activity are required for the cells’ motility. Biochemical assays indicated that MPST acts by protecting protein cysteine residues from dismal hyperoxidation. In vivo, MPST knockdown translated in reduced tumor burden, and a robust increase in mice survival. These results show that enhanced oxidative stress coupled with MPST mobilization plays a key role in glioblastoma cell motility.

Published
2022
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15. Study of LAT1 Expression in Brain Metastases: Towards a Better Understanding of the Results of Positron Emission Tomography Using Amino Acid Tracers.

Author

Caroline Papin-Michault, Christelle Bonnetaud, Maxime Dufour, Fabien Almairac, Mickael Coutts, Stéphanie Patouraux, Thierry Virolle, Jacques Darcourt, and Fanny Burel-Vandenbos

Subjects
Medicine, Science
Abstract

Positron emission tomography using radiolabeled amino acid (PET-AA) appears to be promising in distinguishing between recurrent tumour and radionecrosis in the follow-up of brain metastasis (BM). The amino acid transporter LAT1 and its cofactor CD98, which are involved in AA uptake, have never been investigated in BM. The aim of our study was to determine and compare the expression of LAT1 and CD98 in BM and in non-tumoral brain tissue (NT). The expression of LAT1 and CD98 were studied by immunohistochemistry in 67 BM, including 18 BM recurrences after radiotherapy, in 53 NT, and in 13 cases of patients with previously irradiated brain tumor and investigated by [18F] FDOPA-PET. LAT1 and CD98 expression were detected in 98.5% and 59.7% of BM respectively and were significantly associated with BM tissue as compared to NT (p

Published
2016
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16. Extracellular adenosine promotes cell migration/invasion of Glioblastoma Stem-like Cells through A3 Adenosine Receptor activation under hypoxia

Author

Carlos Spichiger, Claudia Quezada, Ángelo Torres, Pamela Ehrenfeld, Ignacio Niechi, Daniel Uribe, Rody San Martín, Flavio Salazar-Onfray, Fabiola A. Sánchez, Laurent Turchi, José Dellis Rocha, Marcos Ramírez, Thierry Virolle, and José Ignacio Erices

Subjects
0301 basic medicine, Cancer Research, Chemistry, Cell, Cell migration, Hypoxia (medical), Adenosine, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, medicine.anatomical_structure, Oncology, Hypoxia-inducible factors, 030220 oncology & carcinogenesis, Extracellular, medicine, Cancer research, Epithelial–mesenchymal transition, medicine.symptom, Ex vivo, medicine.drug
Abstract

Glioblastoma (GBM) is the brain tumor with the worst prognosis composed of a cell subpopulation called Glioblastoma Stem-like Cells (GSCs) responsible for tumor recurrence mediated by cell invasion. GSCs persist in a hypoxic microenvironment which promotes extracellular adenosine production and activation of the A3 Adenosine Receptor (A3AR), therefore, the aim of this study was to determine the role of extracellular adenosine and A3AR on GSCs invasion under hypoxia. GSCs were obtained from a U87MG cell line and primary cultures of GBM patients, and then incubated under normoxia or hypoxia. Gene expression was evaluated by RNAseq, RT-qPCR, and western blot. Cell migration was measured by spreading and transwell boyden chamber assays; cell invasion was evaluated by Matrigel-coated transwell, ex vivo brain slice, and in vivo xenograft assays. The contribution of A3AR on cell migration/invasion was evaluated using the A3AR antagonist, MRS1220. Extracellular adenosine production was higher under hypoxia than normoxia, mainly by the catalytic action of the prostatic acid phosphatase (PAP), promoting cell migration/invasion in a HIF-2-dependent process. A3AR blockade decreased cell migration/invasion and the expression of Epithelial-Mesenchymal Transition markers. In conclusion, high levels of extracellular adenosine production enhance cell migration/invasion of GSCs, through HIF-2/PAP-dependent activation of A3AR under hypoxia.

Published
2019
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17. ERK-mediated loss of miR-199a-3p and induction of EGR1 act as a 'toggle switch' of GBM cell dedifferentiation into NANOG- and OCT4-positive cells

Author

David Debruyne, Laurent Turchi, Sarah Elkeurti, Marie-Pierre Junier, Thierry Virolle, Fabien Almairac, Hervé Chneiweiss, Philippe Paquis, Laurence Bianchini, Fanny Burel-Vandenbos, Beatrice Polo, Patrick Verrando, Nathalie Sakakini, Elisabet Gjernes, Denys Fontaine, Département de Neurochirurgie [Hôpital Pasteur de Nice], Hôpital Pasteur [Nice] (CHU), Institut de Biologie Valrose (IBV), Université Nice Sophia Antipolis (... - 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)-Centre National de la Recherche Scientifique (CNRS), Dana-Farber Cancer Institute [Boston], Institut de Recherche sur le Cancer et le Vieillissement (IRCAN), 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), Plasticité gliale et neuro-oncologie = Glial Plasticity (NPS-04), Neurosciences Paris Seine (NPS), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-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 National de la Recherche Scientifique (CNRS)-Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Biologie Paris Seine (IBPS), and 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 National de la Recherche Scientifique (CNRS)

Subjects
0301 basic medicine, MAPK/ERK pathway, Homeobox protein NANOG, Cancer Research, [SDV]Life Sciences [q-bio], Population, Cell, EGR1, Biology, 03 medical and health sciences, 0302 clinical medicine, Cancer stem cell, medicine, Humans, education, Early Growth Response Protein 1, education.field_of_study, Cell Differentiation, Nanog Homeobox Protein, Cell cycle, Cell Dedifferentiation, Cell biology, MicroRNAs, 030104 developmental biology, medicine.anatomical_structure, Oncology, 030220 oncology & carcinogenesis, Neoplastic Stem Cells, Signal transduction, Glioblastoma
Abstract

There is great interest in understanding how the cancer stem cell population may be maintained in solid tumors. Here, we show that tumor cells exhibiting stem-like properties and expression of pluripotency markers NANOG and OCT4 can arise from original differentiated tumor cells freshly isolated from human glioblastomas (GBM) and that have never known any serum culture conditions. Induction of EGR1 by EGFR/ERK signaling promoted cell conversion from a less aggressive, more differentiated cellular state to a self-renewing and strongly tumorigenic state, expressing NANOG and OCT4. Expression of these pluripotency markers occurred before the cells re-entered the cell cycle, demonstrating their capacity to change and dedifferentiate without any cell divisions. In differentiated GBM cells, ERK-mediated repression of miR-199a-3p induced EGR1 protein expression and triggered dedifferentiation. Overall, this signaling pathway constitutes an ERK-mediated "toggle switch" that promotes pluripotency marker expression and stem-like features in GBM cells. Significance: This study defines an ERK-mediated molecular mechanism of dedifferentiation of GBM cells into a stem-like state, expressing markers of pluripotency. See related commentary by Koncar and Agnihotri, p. 3195

Published
2020
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18. Cellules souches cancéreuses dans les glioblastomes

Author

Thierry Virolle

Subjects
0301 basic medicine, Cancer Research, business.industry, medicine.medical_treatment, Hematology, General Medicine, Drug resistance, Immunotherapy, medicine.disease, Stem cell niche, 03 medical and health sciences, 030104 developmental biology, Oncology, Cancer stem cell, medicine, Cancer research, Neoplasm, Radiology, Nuclear Medicine and imaging, business, Glioblastoma
Published
2017
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19. Extracellular adenosine promotes cell migration/invasion of Glioblastoma Stem-like Cells through A

Author

Ángelo, Torres, Jose Ignacio, Erices, Fabiola, Sanchez, Pamela, Ehrenfeld, Laurent, Turchi, Thierry, Virolle, Daniel, Uribe, Ignacio, Niechi, Carlos, Spichiger, José Dellis, Rocha, Marcos, Ramirez, Flavio, Salazar-Onfray, Rody, San Martín, and Claudia, Quezada

Subjects
Adenosine, Brain Neoplasms, Acid Phosphatase, Receptor, Adenosine A3, Mice, SCID, Cell Movement, Mice, Inbred NOD, Cell Line, Tumor, Basic Helix-Loop-Helix Transcription Factors, Neoplastic Stem Cells, Tumor Cells, Cultured, Tumor Microenvironment, Animals, Humans, Tumor Hypoxia, Neoplasm Invasiveness, Glioblastoma, Signal Transduction
Abstract

Glioblastoma (GBM) is the brain tumor with the worst prognosis composed of a cell subpopulation called Glioblastoma Stem-like Cells (GSCs) responsible for tumor recurrence mediated by cell invasion. GSCs persist in a hypoxic microenvironment which promotes extracellular adenosine production and activation of the A

Published
2018

20. [Cancer stem cells in glioblastoma]

Author

Thierry, Virolle

Subjects
Mice, Brain Neoplasms, Drug Resistance, Neoplasm, Biomarkers, Tumor, Neoplastic Stem Cells, Animals, Humans, Immunotherapy, Stem Cell Niche, Glioblastoma, Cell Physiological Phenomena
Published
2017

21. DOCK4 promotes loss of proliferation in glioblastoma progenitor cells through nuclear beta-catenin accumulation and subsequent miR-302-367 cluster expression

Author

Philippe Paquis, Laurent Turchi, Thierry Virolle, Mohamed Fareh, P Lagadec, M-P Junier, Denys Fontaine, Dominique Figarella-Branger, Nathalie Baeza-Kallee, Virginie Virolle, Fanny Burel-Vandenbos, V Kubiniek, Hervé Chneiweiss, David Debruyne, Fabien Almairac, Inserm U1091-CNRS U7277, COMUE Université Côte d'Azur (2015-2019) (COMUE UCA), Institut de neurophysiopathologie (INP), Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU), Institut de Biologie Valrose (IBV), Université Nice Sophia Antipolis (... - 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), Institut de Recherche en Cancérologie de Montpellier (IRCM - U1194 Inserm - UM), CRLCC Val d'Aurelle - Paul Lamarque-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Université Nice Sophia Antipolis (1965 - 2019) (UNS), Plasticité gliale et neuro-oncologie = Glial Plasticity (NPS), 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)-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), Institut de Biologie Paris Seine (IBPS), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)

Subjects
0301 basic medicine, Adult, Male, Cancer Research, Beta-catenin, [SDV]Life Sciences [q-bio], Primary Cell Culture, Mitosis, OLIG2, 03 medical and health sciences, Mice, Young Adult, 0302 clinical medicine, Cyclin D1, Mice, Inbred NOD, Genetics, Biomarkers, Tumor, Tumor Cells, Cultured, Animals, Humans, Progenitor cell, RNA, Small Interfering, Molecular Biology, beta Catenin, Cell Proliferation, Cell Nucleus, Feedback, Physiological, Glycogen Synthase Kinase 3 beta, biology, Cell growth, GTPase-Activating Proteins, Dock4, Brain, Oligodendrocyte Transcription Factor 2, Xenograft Model Antitumor Assays, nervous system diseases, MicroRNAs, 030104 developmental biology, Cell culture, 030220 oncology & carcinogenesis, Immunology, biology.protein, Cancer research, Neoplastic Stem Cells, Glioblastoma
Abstract

International audience; Glioblastomas (GBM) are lethal primitive brain tumours characterized by a strong intra-tumour heterogeneity. We observed in GBM tissues the coexistence of functionally divergent micro-territories either enriched in more differentiated and non-mitotic cells or in mitotic undifferentiated OLIG2 positive cells while sharing similar genomic abnormalities. Understanding the formation of such functionally divergent micro-territories in glioblastomas (GBM) is essential to comprehend GBM biogenesis, plasticity and to develop therapies. Here we report an unexpected anti-proliferative role of beta-catenin in non-mitotic differentiated GBM cells. By cell type specific stimulation of miR-302, which directly represses cyclin D1 and stemness features, beta-catenin is capable to change its known proliferative function. Nuclear beta-catenin accumulation in non-mitotic cells is due to a feed forward mechanism between DOCK4 and beta-catenin, allowed by increased GSK3-beta activity. DOCK4 over expression suppresses selfrenewal and tumorigenicity of GBM stem-like cells. Accordingly in the frame of GBM median of survival, increased level of DOCK4 predicts improved patient survival.

Published
2017
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22. [18F] FDOPA standardized uptake values of brain tumors are not exclusively dependent on LAT1 expression

Author

Damien Ambrosetti, Olivier Humbert, Fabien Almairac, John Coyne, Bérengère Dadone-Montaudié, Fanny Burel-Vandenbos, Thierry Virolle, Maxime Dufour, and Jacques Darcourt

Subjects
Male, Fluorine Radioisotopes, Cancer chemotherapy, Cancer Treatment, lcsh:Medicine, Pathology and Laboratory Medicine, 030218 nuclear medicine & medical imaging, Metastasis, Diagnostic Radiology, 0302 clinical medicine, Basic Cancer Research, Medicine and Health Sciences, Blastomas, lcsh:Science, Neurological Tumors, Tomography, Immune Response, Multidisciplinary, medicine.diagnostic_test, Chemistry, Pharmaceutics, Brain Neoplasms, Radiology and Imaging, Brain, Glioma surgery, Glioma, Middle Aged, Immunohistochemistry, Dihydroxyphenylalanine, Oncology, Neurology, Positron emission tomography, 030220 oncology & carcinogenesis, Female, Research Article, Clinical Oncology, Adult, medicine.medical_specialty, Imaging Techniques, Immunology, Radiation Therapy, Neuroimaging, Research and Analysis Methods, 03 medical and health sciences, Cancer Chemotherapy, 18f fdopa, Signs and Symptoms, Drug Therapy, Diagnostic Medicine, medicine, Chemotherapy, Humans, Psychiatry, Aged, Inflammation, business.industry, lcsh:R, Cancers and Neoplasms, Biology and Life Sciences, medicine.disease, Positron-Emission Tomography, Amino Acid Transport Systems, Basic, lcsh:Q, Linear correlation, Clinical Medicine, Radiopharmaceuticals, Nuclear medicine, business, Glioblastoma Multiforme, Positron Emission Tomography, Neuroscience
Abstract

[18F]-FDOPA is a labeled amino acid (AA) analog used for positron emission tomography (PET) which is gaining increasing interest in the evaluation of brain tumors (BT). The AA-transporter LAT1 has been shown to be involved in [18F]-FDOPA uptake. The aim of this study was to determine whether the [18F]-FDOPA uptake was correlated with level of LAT1 expression in BT. Twenty-eight BT (including 19 gliomas and 9 metastases) were investigated by [18F]-FDOPA-PET prior to surgery and by anti-LAT1 immunohistochemistry on surgical specimens. The quantitative [18F]-FDOPA measured parameters were SUVmax, SUVmean and SUVpeak. LAT1 expression was quantified using a score (0 to 400). A significant [18F]-FDOPA uptake was associated with a LAT1 score ≥ 100 (p = 0.02) but there was no linear correlation between intensity of [18F]-FDOPA uptake and score of LAT1 expression whatever the parameters considered. LAT1 expression alone is not sufficient to explain variation of intensity of [18F]-FDOPA uptake in BT.

Published
2017

23. Cell-based therapy using miR-302-367 expressing cells represses glioblastoma growth

Author

Fabien Almairac, Laurent Turchi, Sandra Lacas-Gervais, Fanny Burel-Vandenbos, Marie-Pierre Junier, Hervé Chneiweiss, Philippe Paquis, Mohamed Fareh, Denys Fontaine, Thierry Virolle, Plasticité gliale et neuro-oncologie = Glial Plasticity (NPS-04), Neuroscience 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), 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), Neurosciences Paris Seine (NPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-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)-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)-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)-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
0301 basic medicine, Cancer Research, Cyclin D, Immunology, Cell, Cyclin A, Cell- and Tissue-Based Therapy, Biology, CXCR4, Mice, 03 medical and health sciences, Cellular and Molecular Neuroscience, Glioma, microRNA, medicine, Animals, Humans, E2F1, RNA, Neoplasm, Cell Biology, medicine.disease, Virology, Microvesicles, Neoplasm Proteins, 3. Good health, Gene Expression Regulation, Neoplastic, MicroRNAs, 030104 developmental biology, medicine.anatomical_structure, Multigene Family, Cancer research, biology.protein, Original Article, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Glioblastoma
Abstract

Glioblastomas are incurable primary brain tumors that affect patients of all ages. The aggressiveness of this cancer has been attributed in part to the persistence of treatment-resistant glioblastoma stem-like cells. We have previously discovered the tumor-suppressor properties of the microRNA cluster miR-302-367, representing a potential treatment for glioblastoma. Here, we attempted to develop a cell-based therapy by taking advantage of the capability of glioma cells to secrete exosomes that enclose small RNA molecules. We engineered primary glioma cells to stably express the miR-302-367. Remarkably, these cells altered, in a paracrine-dependent manner, the expression of stemness markers, the proliferation and the tumorigenicity of neighboring glioblastoma cells. Further characterization of the secretome derived from miR-302-367 expressing cells showed that a large amount of miR-302-367 was enclosed in exosomes, which were internalized by the neighboring glioblastoma cells. This miR-302-367 cell-to-cell transfer resulted in the inhibition of its targets such as CXCR4/SDF1, SHH, cyclin D, cyclin A and E2F1. Orthotopic xenograft of miR-302-367-expressing cells together with glioblastoma stem-like cells efficiently altered the tumor development in mice brain.

Published
2017
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24. A Positive Feed-forward Loop Associating EGR1 and PDGFA Promotes Proliferation and Self-renewal in Glioblastoma Stem Cells

Author

Ellen Van Obberghen-Schilling, Thierry Virolle, Fabien Almairac, Hervé Chneiweiss, Nathalie Sakakini, Aurélie Bergon, Jean Imbert, Hélène Holota, Samah Rekima, Denys Fontaine, Dominique Figarella-Branger, Philippe Paquis, Marie-Pierre Junier, Fanny Burel-Vandenbos, Fabrice Lopez, Laurent Turchi, Nathalie Baeza-Kallee, Technologies avancées pour le génôme et la clinique (TAGC), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Département de Neurochirurgie [Hôpital Pasteur de Nice], Hôpital Pasteur [Nice] (CHU), 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), Institut de Biologie Valrose (IBV), 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), Neuroscience 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), Plasticité gliale et neuro-oncologie = Glial Plasticity (NPS-04), 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), Hôpital de la Timone [CHU - APHM] (TIMONE), Service de pathologie, Centre Hospitalier Universitaire de Nice (CHU Nice), Evolution et Diversité Biologique (EDB), Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS), Université Nice Sophia Antipolis (... - 2019) (UNS), Neurosciences Paris Seine (NPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-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)-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)-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)-Institut de Biologie Paris Seine (IBPS), Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Nice Sophia Antipolis (... - 2019) (UNS), Université Côte d'Azur (UCA)-Université Côte d'Azur (UCA), 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), 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), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), Aix Marseille Université (AMU) - Institut National de la Santé et de la Recherche Médicale (INSERM) - Centre National de la Recherche Scientifique (CNRS), Fac de Médecine, ENFA, CNRS, UMR5174, Lab Evolut & Diversite Biol, Université Paul Sabatier - Toulouse 3 (UPS), Aix Marseille Université (AMU) - Hôpital de la Timone [CHU - APHM] (TIMONE) - Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de signalisation, biologie du développement et cancer (ISBDC), Centre National de la Recherche Scientifique (CNRS) - Université Nice Sophia Antipolis (UNS) - Université Côte d'Azur (UCA), Centre de Psychiatrie et Neurosciences (CPN - UMR_S 894), Université Paris Descartes - Paris 5 (UPD5) - Institut National de la Santé et de la Recherche Médicale (INSERM), 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), Service d’Anatomopathologie, and CHU Nice

Subjects
0301 basic medicine, Male, endocrine system, [SDV]Life Sciences [q-bio], EGR1, Biology, Biochemistry, 03 medical and health sciences, Cancer stem cell, GLI1, GLI2, Glioma, medicine, Tumor Cells, Cultured, Humans, Gene Regulation, Progenitor cell, Molecular Biology, neoplasms, ComputingMilieux_MISCELLANEOUS, Cell Proliferation, Early Growth Response Protein 1, Zinc finger transcription factor, Platelet-Derived Growth Factor, Brain Neoplasms, Cell Biology, medicine.disease, 3. Good health, Neoplasm Proteins, nervous system diseases, [SDV] Life Sciences [q-bio], Gene Expression Regulation, Neoplastic, Autocrine Communication, 030104 developmental biology, Immunology, Cancer research, biology.protein, Neoplastic Stem Cells, Female, Stem cell, Glioblastoma
Abstract

International audience; Glioblastomas are the most common primary brain tumors, highly vascularized, infiltrating, and resistant to current therapies. This cancer leads to a fatal outcome in less than 18 months. The aggressive behavior of glioblastomas, including resistance to current treatments and tumor recurrence, has been attributed to glioma stemlike/progenitor cells. The transcription factor EGR1 (early growth response 1), a member of a zinc finger transcription factor family, has been described as tumor suppressor in gliomas when ectopically overexpressed. Although EGR1 expression in human glioblastomas has been associated with patient survival, its precise location in tumor territories as well as its contribution to glioblastoma progression remain elusive. In the present study, we show that EGR1-expressing cells are more frequent in high grade gliomas where the nuclear expression of EGR1 is restricted to proliferating/progenitor cells. We show in primary cultures of glioma stemlike cells that EGR1 contributes to stemness marker expression and proliferation by orchestrating a PDGFA-dependent growth-stimulatory loop. In addition, we demonstrate that EGR1 acts as a positive regulator of several important genes, including SHH, GLI1, GLI2, and PDGFA, previously linked to the maintenance and proliferation of glioma stemlike cells.

Published
2016
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25. Study of LAT1 Expression in Brain Metastases: Towards a Better Understanding of the Results of Positron Emission Tomography Using Amino Acid Tracers

Author

Christelle Bonnetaud, Caroline Papin-Michault, Fabien Almairac, Jacques Darcourt, Stéphanie Patouraux, Mickael Coutts, Maxime Dufour, Thierry Virolle, and Fanny Burel-Vandenbos

Subjects
Male, Pathology, lcsh:Medicine, Squamous Cell Lung Carcinoma, Lung and Intrathoracic Tumors, 030218 nuclear medicine & medical imaging, Diagnostic Radiology, 0302 clinical medicine, Adenocarcinomas, Medicine and Health Sciences, Neoplasm Metastasis, lcsh:Science, Neurological Tumors, Tomography, Multidisciplinary, medicine.diagnostic_test, biology, Adenocarcinoma of the Lung, Brain Neoplasms, Radiology and Imaging, Squamous Cell Carcinomas, Dihydroxyphenylalanine, Neoplasm Proteins, Gene Expression Regulation, Neoplastic, Oncology, Neurology, Positron emission tomography, 030220 oncology & carcinogenesis, Large-cell lung carcinoma, Immunohistochemistry, Female, Large Cell Lung Carcinoma, Research Article, CD98, medicine.medical_specialty, Imaging Techniques, Brain tumor, Neuroimaging, Research and Analysis Methods, Carcinomas, Large Neutral Amino Acid-Transporter 1, 03 medical and health sciences, Diagnostic Medicine, medicine, Adenocarcinoma of the lung, Humans, Amino acid transporter, Radioactive Tracers, business.industry, lcsh:R, Cancers and Neoplasms, Biology and Life Sciences, medicine.disease, Molecular biology, Positron-Emission Tomography, biology.protein, Brain Metastasis, lcsh:Q, Radiopharmaceuticals, business, Positron Emission Tomography, Brain metastasis, Neuroscience
Abstract

Positron emission tomography using radiolabeled amino acid (PET-AA) appears to be promising in distinguishing between recurrent tumour and radionecrosis in the follow-up of brain metastasis (BM). The amino acid transporter LAT1 and its cofactor CD98, which are involved in AA uptake, have never been investigated in BM. The aim of our study was to determine and compare the expression of LAT1 and CD98 in BM and in non-tumoral brain tissue (NT). The expression of LAT1 and CD98 were studied by immunohistochemistry in 67 BM, including 18 BM recurrences after radiotherapy, in 53 NT, and in 13 cases of patients with previously irradiated brain tumor and investigated by [18F] FDOPA-PET. LAT1 and CD98 expression were detected in 98.5% and 59.7% of BM respectively and were significantly associated with BM tissue as compared to NT (p

Published
2016

26. MET immunolabelling is a useful predictive tool for MET gene amplification in glioblastoma

Author

S. Gimet, I. Di Mauro, Thierry Virolle, Véronique Bourg, Esma Saada-Bouzid, Fanny Burel-Vandenbos, Fabien Almairac, Denys Fontaine, Florence Pedeutour, M. Ngo-Mai, and B. Dadone

Subjects
0301 basic medicine, Adult, Male, Pathology, medicine.medical_specialty, Histology, Microarray, In situ hybridization, Bioinformatics, Pathology and Forensic Medicine, Cohort Studies, 03 medical and health sciences, 0302 clinical medicine, Physiology (medical), Gene duplication, Biomarkers, Tumor, Medicine, Humans, Aged, business.industry, Brain Neoplasms, Gene Amplification, Middle Aged, Proto-Oncogene Proteins c-met, Immunohistochemistry, 030104 developmental biology, Neurology, 030220 oncology & carcinogenesis, Cohort, Female, Neurology (clinical), business, Glioblastoma, Immunostaining, Cohort study, Comparative genomic hybridization
Abstract

Aims MET gene amplification is rare in glioblastoma (GBM) and represents a potential target for MET inhibitors. An immunohistochemical screening may be useful to identify MET amplification. The aim of our study was to establish how MET immunolabelling correlates with MET amplification. Methods Three cohorts including 108 GBM (cohort 1, prospective), 104 GBM (cohort 2, retrospective) and 52 GBM (cohort 3, prospective) were investigated for MET expression by immunohistochemistry. MET amplification was assessed by comparative genomic hybridization on microarray (CGH-array) in all cohorts and by fluorescent in situ hybridization (FISH) in cohorts 2 and 3. Active form of MET was assessed using p-MET (Y1349) immunohistochemistry. Results Diffuse MET amplification detectable by CGH-array was associated with diffuse, strong MET immunolabelling (four cases in cohort 1 and one case in cohort 2). Focal MET amplification detectable only by FISH was observed in small foci of strongly immunopositive cells in two GBM (cohort 2). In both cohorts, MET amplification was never detected in GBM devoid of strongly immunopositive cells. MET overexpression, observed in 23% of unamplified GBM, was associated with a predominant weak-to-moderate staining intensity and with necrosis (P < 0.005). p-MET was detected in all MET-amplified GBM and in perinecrotic areas of nonamplified GBM. A strong MET immunostaining intensity, at least focal and distant from necrosis, showed 100% sensitivity and 84% specificity for predicting MET amplification in cohort 3. Conclusions MET amplification is characterized by strongly immunopositive cells. Only GBM showing strong MET immunostaining is appropriate for the assessment of MET amplification.

Published
2015

27. Plasticité des cellules tumorales de glioblastomes : inter-conversion d’un phénotype différencié et souche en fonction du microenvironnement

Author

Almairac, Fabien, Institut de Biologie Valrose (IBV), Université Nice Sophia Antipolis (... - 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), Université Nice Sophia Antipolis, and Thierry Virolle

Subjects
Glioblastome, [SDV.SA]Life Sciences [q-bio]/Agricultural sciences, Plasticity, Plasticité, Micro-RNA, Cellules souches cancéreuses, Glioblastoma, Micro-ARN, Exosomes, Cancer Stem-Cell, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract

There is great interest but little understanding in how cancer stem cells arise. Here we show that tumor cells exhibiting stem-like properties and expression of stemness(CD133) and pluripotency markers (SOX2, NANOG, OCT4), can arise from differentiated tumor cells that are isolated from human glioblastomas. These cells could transit from a more differentiated state that cannot self-renew to a self-renewing stem-like state upon EGF/EGFR signaling. This dedifferentiation process induced expression of pluripotency markers, and restored clonal and tumorigenic properties as well as resistance to temozolomide, the chemotherapy of reference. EGF/EGFR signaling including ERK activation was crucial for this cellular reprogramming. Interestingly, expression of pluripotency markers occurred before the cells re-entered the cell cycle, demonstrating that the cells have the capacity to change and reprogram before the cell division starts. Our findings support a model of tumor homeostasis in which tumor cells driven by environmental cues such as EGF, can spontaneously acquire stem-like properties contributing thus to the enrichment in tumor propagating cells.; L’objectif de ce travail était de démontrer que les cellules de glioblastomes sont capables de se différencier et de se dédifférencier en fonction de leur environnement, d’explorer les mécanismes biologiques qui sous-tendent ces transitions, et d’évaluer in vivo les capacités de différenciation à distance des CIG par les CIG-miR-302-367 via la sécrétion de microvésicules. A partir de plusieurs glioblastomes fraichement réséqués, nous avons caractérisé les cellules tumorales sur le plan phénotypique et fonctionnel pour l’état souche et différencié. Nous avons extraits et analysés les microvésicules des milieux de culture de 2 lignées de CIG-miR-302-367. Selon les principes de la thérapie cellulaire, des co-injections de CIG+CIG-miR-302-367 ont été réalisées dans le cerveau des souris. La majorité des cellules tumorales avaient un phénotype et étaient fonctionnellement différenciées. Après 48 heures de culture en milieu EGF, elles acquéraient les propriétés souches phénotypiques et fonctionnelles. Ce processus de dédifférenciation était réversible en 4 jours de culture en milieu sérum et inhibé par l’adjonction dans le milieu EGF d’un anti-EGFR (cétuximab), suggérant un rôle primordial de la voie EGF/EGFR/ERK. Les microvésicules produites par les CIG-miR-302-367 ont permis une baisse significative de la tumorigénicité des CIG in vivo, et une augmentation de la survie des souris. Le concept de plasticité cellulaire remet en cause les dogmes établis sur la hiérarchie tumorale unidirectionnelle. La déplétion tumorale en CIG, en les forçant à se différencier, est une stratégie thérapeutique innovante, qui peut s’envisager par une approche de thérapie cellulaire.

Published
2016

28. EGF/EGFR pathway is sufficient to induce aggressiveness and expression of pluripotency markers of patient-derived glioblastoma cells

Author

Almairac, Fabien, Institut de Biologie Valrose (IBV), Université Nice Sophia Antipolis (... - 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), Université Nice Sophia Antipolis, and Thierry Virolle

Subjects
Glioblastome, [SDV.SA]Life Sciences [q-bio]/Agricultural sciences, Plasticity, Plasticité, Micro-RNA, Cellules souches cancéreuses, Glioblastoma, Micro-ARN, Exosomes, Cancer Stem-Cell, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract

There is great interest but little understanding in how cancer stem cells arise. Here we show that tumor cells exhibiting stem-like properties and expression of stemness(CD133) and pluripotency markers (SOX2, NANOG, OCT4), can arise from differentiated tumor cells that are isolated from human glioblastomas. These cells could transit from a more differentiated state that cannot self-renew to a self-renewing stem-like state upon EGF/EGFR signaling. This dedifferentiation process induced expression of pluripotency markers, and restored clonal and tumorigenic properties as well as resistance to temozolomide, the chemotherapy of reference. EGF/EGFR signaling including ERK activation was crucial for this cellular reprogramming. Interestingly, expression of pluripotency markers occurred before the cells re-entered the cell cycle, demonstrating that the cells have the capacity to change and reprogram before the cell division starts. Our findings support a model of tumor homeostasis in which tumor cells driven by environmental cues such as EGF, can spontaneously acquire stem-like properties contributing thus to the enrichment in tumor propagating cells.; L’objectif de ce travail était de démontrer que les cellules de glioblastomes sont capables de se différencier et de se dédifférencier en fonction de leur environnement, d’explorer les mécanismes biologiques qui sous-tendent ces transitions, et d’évaluer in vivo les capacités de différenciation à distance des CIG par les CIG-miR-302-367 via la sécrétion de microvésicules. A partir de plusieurs glioblastomes fraichement réséqués, nous avons caractérisé les cellules tumorales sur le plan phénotypique et fonctionnel pour l’état souche et différencié. Nous avons extraits et analysés les microvésicules des milieux de culture de 2 lignées de CIG-miR-302-367. Selon les principes de la thérapie cellulaire, des co-injections de CIG+CIG-miR-302-367 ont été réalisées dans le cerveau des souris. La majorité des cellules tumorales avaient un phénotype et étaient fonctionnellement différenciées. Après 48 heures de culture en milieu EGF, elles acquéraient les propriétés souches phénotypiques et fonctionnelles. Ce processus de dédifférenciation était réversible en 4 jours de culture en milieu sérum et inhibé par l’adjonction dans le milieu EGF d’un anti-EGFR (cétuximab), suggérant un rôle primordial de la voie EGF/EGFR/ERK. Les microvésicules produites par les CIG-miR-302-367 ont permis une baisse significative de la tumorigénicité des CIG in vivo, et une augmentation de la survie des souris. Le concept de plasticité cellulaire remet en cause les dogmes établis sur la hiérarchie tumorale unidirectionnelle. La déplétion tumorale en CIG, en les forçant à se différencier, est une stratégie thérapeutique innovante, qui peut s’envisager par une approche de thérapie cellulaire.

Published
2016

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