Search

Your search keyword '"Thierry, Virolle"' showing total 20 results
Start Over Author "Thierry, Virolle" Language english
20 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
Full Text
View/download PDF

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
Full Text
View/download PDF

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
Full Text
View/download PDF

4. 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
Full Text
View/download PDF

5. [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
Full Text
View/download PDF

6. 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
Full Text
View/download PDF

7. 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
Full Text
View/download PDF

8. DeltaNp63 is essential for epidermal commitment of embryonic stem cells.

Author

Alain Medawar, Thierry Virolle, Philippe Rostagno, Stéphanie de la Forest-Divonne, Karen Gambaro, Matthieu Rouleau, and Daniel Aberdam

Subjects
Medicine, Science
Abstract

In vivo studies have demonstrated that p63 plays complex and pivotal roles in pluristratified squamous epithelial development, but its precise function and the nature of the isoform involved remain controversial. Here, we investigate the role of p63 in epithelial differentiation, using an in vitro ES cell model that mimics the early embryonic steps of epidermal development. We show that the DeltaNp63 isoform is activated soon after treatment with BMP-4, a morphogen required to commit differentiating ES cells from a neuroectodermal to an ectodermal cell fate. DeltaNp63 gene expression remains high during epithelial development. P63 loss of function drastically prevents ectodermal cells to commit to the K5/K14-positive stratified epithelial pathway while gain of function experiments show that DeltaNp63 allows this commitment. Interestingly, other epithelial cell fates are not affected, allowing the production of K5/K18-positive epithelial cells. Therefore, our results demonstrate that DeltaNp63 may be dispensable for some epithelial differentiation, but is necessary for the commitment of ES cells into K5/K14-positive squamous stratified epithelial cells.

Published
2008
Full Text
View/download PDF

9. 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
Full Text
View/download PDF

10. [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

11. 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
Full Text
View/download PDF

12. 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
Full Text
View/download PDF

13. 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

14. The relationship between brain tumor cell invasion of engineered neural tissues and in vivo features of glioblastoma

Author

Hedi Peterson, Thierry Virolle, Karl-Heinz Krause, Pierre-Yves Dietrich, Olivier Preynat-Seauve, Diderik Tirefort, Valérie Dutoit, Hervé Chneiweiss, Laurent Turchi, Johannes Alexander Lobrinus, Erika Cosset, Zeynab Nayernia, 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 de Genève = University of Geneva (UNIGE), Université Nice Sophia Antipolis (1965 - 2019) (UNS), 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
neural cell, Pathology, medicine.medical_specialty, Programmed cell death, in vitro test, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Biophysics, Brain tumor, [SDV.CAN]Life Sciences [q-bio]/Cancer, Bioengineering, Biology, ddc:616.07, Polymerase Chain Reaction, Cell Line, Biomaterials, Mice, 03 medical and health sciences, 0302 clinical medicine, Pregnancy, Interferon, In vivo, medicine, Animals, Humans, [SDV.IB.BIO]Life Sciences [q-bio]/Bioengineering/Biomaterials, Induced pluripotent stem cell, [SDV.BDD]Life Sciences [q-bio]/Development Biology, Cells, Cultured, 030304 developmental biology, ddc:616, 0303 health sciences, Tissue Engineering, Brain Neoplasms, Stem Cells, Nervous tissue, medicine.disease, Immunohistochemistry, Primary tumor, stem cell, medicine.anatomical_structure, Mechanics of Materials, 030220 oncology & carcinogenesis, Ceramics and Composites, nerve tissue engineering, Female, Stem cell, Glioblastoma, medicine.drug
Abstract

International audience; Glioblastoma is an aggressive brain tumor characterized by its high propensity for local invasion, formation of secondary foci within the brain, as well as areas of necrosis. This study aims to (i) provide a technical approach to reproduce features of the disease in vitro and (ii) characterize the tumor/host brain tissue interaction at the molecular level. Human engineered neural tissue (ENT) obtained from pluripotent stem cells was generated and co-cultured with human glioblastoma-initiating cells. Within two weeks, glioblastoma cells invaded the nervous tissue. This invasion displayed features of the disease in vivo: a primary tumor mass, diffuse migration of invading single cells into the nervous tissue, secondary foci, as well as peritumoral cell death. Through comparative molecular analyses, this model allowed the identification of more than 100 genes that are specifically induced and up-regulated by the nervous tissue/tumor interaction. Notably the type I interferon response, extracellular matrix-related genes were most highly represented and showed a significant correlation with patient survival. In conclusion, glioblastoma development within a nervous tissue can be engineered in vitro, providing a relevant model to study the disease and allows the identification of clinically-relevant genes induced by the tumor/host tissue interaction.

Published
2013
Full Text
View/download PDF

15. Cells with intense EGFR staining and a high nuclear to cytoplasmic ratio are specific for infiltrative glioma: a useful marker in neuropathological practice

Author

Fanny Burel-Vandenbos, Maxime Benchetrit, Fabien Almairac, E. Fontas, Damien Ambrosetti, Laurent Turchi, Valérie Rigau, Jean-François Michiels, Thierry Virolle, Zoe Pedeutour, Institut de Biologie Valrose (IBV), Université Nice Sophia Antipolis (... - 2019) (UNS), and 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)

Subjects
Adult, Male, Cancer Research, Pathology, medicine.medical_specialty, Cytoplasm, IDH1, Blotting, Western, Fluorescent Antibody Technique, Glial tumor, Biology, Immunoenzyme Techniques, 03 medical and health sciences, 0302 clinical medicine, Glioma, Biopsy, medicine, Biomarkers, Tumor, Tumor Cells, Cultured, Humans, Progenitor cell, Child, [SDV.BDD]Life Sciences [q-bio]/Development Biology, In Situ Hybridization, Fluorescence, Retrospective Studies, Cell Nucleus, medicine.diagnostic_test, Brain Neoplasms, medicine.disease, Flow Cytometry, 3. Good health, ErbB Receptors, Oncology, Gliosis, 030220 oncology & carcinogenesis, Basic and Translational Investigations, Immunohistochemistry, Female, Neurology (clinical), medicine.symptom, 030217 neurology & neurosurgery, Immunostaining
Abstract

Infiltrative gliomas (IG), including astrocytomas, oligodendrogliomas, and glioblastomas, are the most common primary brain tumors in humans.1 IG display a poor prognosis, especially glioblastomas, which represent the most aggressive subtype.1 The tumors of this group are characterized by a pattern of infiltrative growth into the surrounding normal brain,2 making complete surgical excision very difficult. Recurrence or progression after surgery almost always occurs despite adjuvant treatment with radiotherapy and/or chemotherapy.1 Morphological patterns of IG are often heterogeneous, and the diagnosis may be challenging for pathologists.2 Glial tumor cells may also be difficult to distinguish from reactive cells on the basis of morphology alone. Reactive astrocytes may become very large and may even display pleomorphic nuclei resembling neoplastic tumor cells.3 The differential diagnosis between IG and gliosis can thus be difficult, especially in small biopsy samples.4 IG can also be difficult to differentiate from benign and/or curable noninfiltrative glial tumors, including pilocytic astrocytomas, gangliogliomas, and dysembryoplastic neuroepithelial tumors,1,2 and from demyelinating disease.5 It is therefore very important for pathologists to develop histological markers to identify infiltrating glioma cells. To date, no ideal marker has been identified for this purpose. In practice, the most useful markers are MIB1/Ki676,7 and p53,8,9 but these lack sensitivity and specificity.10 More recently, the mutated R132H form of isocitrate dehydrogenase 1 (IDH1), which can be specifically detected by immunohistochemistry,11,12 has been shown to be a good marker of grade II and grade III gliomas and of secondary glioblastomas.13–15 However IDH1 (R132H) is rare in primary glioblastomas16 and is not useful for the diagnosis of this subtype, which represents the most common IG. A marker specific for infiltrating cells, which are characteristic of IG regardless of grade or histological subtype, would be of value. Recently, we showed that the EGFR immunolabelling pattern can discriminate low-grade glioma from gliosis.17 The criterion that characterized low-grade gliomas was strong EGFR immunostaining in cells with a high nuclear to cytoplasmic ratio. EGFR overexpression is frequent in gliomas. In 40% of glioblastomas, EGFR overexpression is secondary to gene amplification and is often associated with expression of EGFRvIII, a constitutively activated mutated variant.18 Conversely, EGFR amplification is rare in low-grade gliomas,18–21 although protein overexpression has been detected with a frequency ranging from 11.5% to 100% of cases in the literature.19,20,22–24 The mechanism of this overexpression in low-grade IG remains unknown. Several ligands, including EGF and TGFα, may activate EGFR. The activation of EGFR is involved in several processes, including cell survival, differentiation, proliferation, and migration.25 Because EGFR has been shown to influence cell migration during the development of the central nervous system26–28 and in gliomas,29–31 we postulated that EGFR could be a marker of migrating cells, specific for IG. The aim of the present study was to assess whether elevated EGFR expression in cells with a high nuclear to cytoplasmic ratio, as we previously observed in low-grade glioma,17 may be a valuable criterion to discriminate infiltrative gliomas of any grade or histological subtype from noninfiltrative glial lesions. We also sought to further characterize these strongly EGFR-positive cells.

Published
2013
Full Text
View/download PDF

16. Fibronectin expression in glioblastomas promotes cell cohesion, collective invasion of basement membrane in vitro and orthotopic tumor growth in mice

Author

Franck Debarbieux, Geneviève Rougon, Dominique Grall, E Serres, Dominique Figarella-Branger, Thierry Virolle, Fabio Stanchi, Laurent Turchi, Laurence Maggiorella, E Van Obberghen-Schilling, Fanny Burel-Vandenbos, Centre de Physique des Particules de Marseille (CPPM), Aix Marseille Université (AMU)-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Centre National de la Recherche Scientifique (CNRS), Institut de Biologie du Développement de Marseille (IBDM), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Vectorologie et transfert de gènes (VTG / UMR8121), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Centre National de la Recherche Scientifique (CNRS), Institut de signalisation, biologie du développement et cancer (ISBDC), Centre National de la Recherche Scientifique (CNRS)-Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Université Côte d'Azur (UCA), Physiopathologie et biothérapie: cellules souches, développement et cancer, Institut National de la Santé et de la Recherche Médicale (INSERM), IFR50, Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Faculté de Médecine Nice, Service d'anatomie pathologique et de neurophatologie, Assistance Publique - Hôpitaux de Marseille (APHM)-CHU Marseille, Centre de référence des maladies rares neuromusculaires, Université Nice Sophia Antipolis (1965 - 2019) (UNS), and 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)

Subjects
Cancer Research, Angiogenesis, Cell Survival, Cell, Motility, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Biology, Basement Membrane, Small hairpin RNA, Extracellular matrix, Mice, Cell Movement, Spheroids, Cellular, Genetics, medicine, Cell Adhesion, Tumor Cells, Cultured, Animals, Humans, Protein Isoforms, Neoplasm Invasiveness, RNA, Small Interfering, Cell adhesion, Molecular Biology, Cell Proliferation, Neovascularization, Pathologic, Cell growth, Extracellular Matrix, Fibronectins, Fibronectin, Gene Expression Regulation, Neoplastic, medicine.anatomical_structure, Immunology, biology.protein, Cancer research, RNA Interference, Glioblastoma, Integrin alpha5beta1
Abstract

International audience; : Glioblastoma multiforme (GBM) are highly invasive and angiogenic malignancies with a median survival time from diagnosis of

Published
2013
Full Text
View/download PDF

17. Tumorigenic Potential of miR-18A* in Glioma Initiating Cells Requires NOTCH-1 Signaling

Author

Mohamed Fareh, Philippe Paquis, Ellen Van Obberghen-Schilling, Marie-Pierre Junier, Laurent Turchi, Thierry Virolle, Fanny Burel-Vandenbos, Yasmine Neirijnck, Fabien Almairac, Hervé Chneiweiss, Virginie Virolle, David Debruyne, 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), and Université Nice Sophia Antipolis (1965 - 2019) (UNS)

Subjects
Male, MAPK/ERK pathway, Cell type, MAP Kinase Signaling System, Cellular differentiation, Down-Regulation, Cell Growth Process, Cell Growth Processes, Biology, Transfection, Bioinformatics, Mice, 03 medical and health sciences, 0302 clinical medicine, Mice, Inbred NOD, microRNA, Animals, Humans, Hedgehog Proteins, Receptor, Notch1, Autocrine signalling, Notch 1, [SDV.BDD]Life Sciences [q-bio]/Development Biology, Aged, 030304 developmental biology, 0303 health sciences, Intracellular Signaling Peptides and Proteins, Membrane Proteins, Cell Differentiation, Glioma, Cell Biology, Middle Aged, Cell biology, MicroRNAs, 030220 oncology & carcinogenesis, Molecular Medicine, Stem cell, Developmental Biology
Abstract

Stem cell-like properties of glioma initiating cells (GiCs) fuel glioblastoma (GBM) development by providing the different cell types that comprise the tumor. It is therefore likely that the molecular circuitries that regulate their decision to self-renew or commit to a more differentiated state may offer targets for future innovative therapies. In previous micro-RNA profiling studies to search for regulators of stem cell plasticity, we identified miR-18a* as a potential candidate and its expression correlated with the stemness state. Here, using human GiCs we found that miR-18a* expression promotes clonal proliferation in vitro and tumorigenicity in vivo. Mechanistically, ERK-dependent induction of miR-18a* directly represses expression of DLL3, an autocrine inhibitor of NOTCH, thus enhancing the level of activated NOTCH-1. Activated NOTCH-1 in turn is required for sustained ERK activation. This feed-forward loop, driven by miR-18a*, is required to turn on the SHH-GLI-NANOG network, essential for GiC self-renewal. Hence, by tightly regulating expression of DLL3, miR-18a* constitutes an important signaling mediator for fine tuning the level of GiC self-renewal.

Published
2013
Full Text
View/download PDF

18. The miR 302-367 cluster drastically affects self-renewal and infiltration properties of Glioma-initiating cells through CXCR4 repression and consequent disruption of the SHH-GLI-NANOG network

Author

Laurent Turchi, Olivier Preynat-Seauve, S de-la-Forest Divonne, Hervé Chneiweiss, Virginie Virolle, Philippe Paquis, Fabien Almairac, Thierry Virolle, David Debruyne, K-H Krause, Mohamed Fareh, and Fac de Médecine

Subjects
Serum, cancer stem cells, Tumor initiation, ddc:616.07, self-renewal, infiltration, Mice, 0302 clinical medicine, Cell Movement, Sonic hedgehog, Regulation of gene expression, 0303 health sciences, biology, Neoplastic Stem Cells/metabolism/pathology, Receptors, CXCR4/genetics/metabolism, Glioma, Multigene Family/genetics, Cell biology, Gene Expression Regulation, Neoplastic, Cell Transformation, Neoplastic, 030220 oncology & carcinogenesis, Multigene Family, Neoplastic Stem Cells, cxcr4, Signal Transduction, Homeobox protein NANOG, Receptors, CXCR4, Cell Transformation, Neoplastic/pathology, Down-Regulation, 03 medical and health sciences, Cancer stem cell, Cell Line, Tumor, medicine, Animals, Humans, Cell Lineage, Molecular Biology, 030304 developmental biology, Cell Proliferation, miRNA, Original Paper, Cell growth, Glioma/genetics/pathology, Cell Biology, medicine.disease, Embryonic stem cell, MicroRNAs/genetics, MicroRNAs, Immunology, biology.protein
Abstract

Glioblastoma multiforme (GBM) is the most common form of primary brain tumor in adults, often characterized by poor survival. Glioma-initiating cells (GiCs) are defined by their extensive self-renewal, differentiation, and tumor initiation properties. GiCs are known to be involved in tumor growth and recurrence, and in resistance to conventional treatments. One strategy to efficiently target GiCs in GBM consists in suppressing their stemness and consequently their tumorigenic properties. In this study, we show that the miR-302-367 cluster is strongly induced during serum-mediated stemness suppression. Stable miR-302-367 cluster expression is sufficient to suppress the stemness signature, self-renewal, and cell infiltration within a host brain tissue, through inhibition of the CXCR4 pathway. Furthermore, inhibition of CXCR4 leads to the disruption of the sonic hedgehog (SHH)-GLI-NANOG network, which is involved in self-renewal and expression of the embryonic stem cell-like signature. In conclusion, we demonstrated that the miR-302-367 cluster is able to efficiently trigger a cascade of inhibitory events leading to the disruption of GiCs stem-like and tumorigenic properties.

Published
2011
Full Text
View/download PDF

19. ΔNp63 Is Essential for Epidermal Commitment of Embryonic Stem Cells

Author

Matthieu Rouleau, Thierry Virolle, Stéphanie de la Forest-Divonne, Philippe Rostagno, Alain Medawar, Daniel Aberdam, and Karen Gambaro

Subjects
Cellular differentiation, Cell Biology/Developmental Molecular Mechanisms, Morphogenesis, lcsh:Medicine, Dermatology, Bone Morphogenetic Protein 4, Biology, Transfection, Mice, medicine, Animals, Humans, lcsh:Science, Embryonic Stem Cells, Multidisciplinary, Epidermis (botany), integumentary system, lcsh:R, Cell Differentiation, Phosphoproteins, Embryonic stem cell, Epithelium, Cell biology, medicine.anatomical_structure, Bone morphogenetic protein 4, Epidermal Cells, Developmental Biology/Cell Differentiation, NIH 3T3 Cells, Trans-Activators, lcsh:Q, Morphogen, Research Article, HeLa Cells
Abstract

In vivo studies have demonstrated that p63 plays complex and pivotal roles in pluristratified squamous epithelial development, but its precise function and the nature of the isoform involved remain controversial. Here, we investigate the role of p63 in epithelial differentiation, using an in vitro ES cell model that mimics the early embryonic steps of epidermal development. We show that the DeltaNp63 isoform is activated soon after treatment with BMP-4, a morphogen required to commit differentiating ES cells from a neuroectodermal to an ectodermal cell fate. DeltaNp63 gene expression remains high during epithelial development. P63 loss of function drastically prevents ectodermal cells to commit to the K5/K14-positive stratified epithelial pathway while gain of function experiments show that DeltaNp63 allows this commitment. Interestingly, other epithelial cell fates are not affected, allowing the production of K5/K18-positive epithelial cells. Therefore, our results demonstrate that DeltaNp63 may be dispensable for some epithelial differentiation, but is necessary for the commitment of ES cells into K5/K14-positive squamous stratified epithelial cells.

Published
2008

20. Hif-2alpha mediates UV-induced apoptosis through a novel ATF3-dependent death pathway

Author

Laurent Turchi, Daniel Aberdam, Marcel Deckert, Jacques Pouysségur, Shigetaka Kitajima, Edith Aberdam, Nathalie M. Mazure, Thierry Virolle, IFR50, Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Faculté de Médecine Nice, Physiopathologie et biothérapie: cellules souches, développement et cancer, 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 (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Université Côte d'Azur (UCA), Régulations des réactions immunitaires et inflammatoires, COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-IFR50-Institut National de la Santé et de la Recherche Médicale (INSERM), Dept. of Biochemical Genetics, and Tokyo Medical and Dental University

Subjects
Cancer Research, Programmed cell death, Ultraviolet Rays, p38 mitogen-activated protein kinases, Activating transcription factor, Apoptosis, [SDV.CAN]Life Sciences [q-bio]/Cancer, Biology, 03 medical and health sciences, Mice, 0302 clinical medicine, Basic Helix-Loop-Helix Transcription Factors, Animals, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, RNA, Messenger, Molecular Biology, Cells, Cultured, 030304 developmental biology, Regulation of gene expression, 0303 health sciences, ATF3, Activating Transcription Factor 3, Chemistry, Effector, Cell Biology, Hypoxia-Inducible Factor 1, alpha Subunit, Cell biology, Oncology, Hypoxia-inducible factors, 030220 oncology & carcinogenesis, Apoptosis Regulatory Proteins, Signal Transduction
Abstract

In this study, we describe a novel activating transcription factor 3 (ATF3)-dependent death pathway triggered by ultraviolet (UV) irradiation. We demonstrate that ATF3 contributes to UV-induced apoptosis through the regulation of hypoxia inducible factor (Hif)-2alpha expression, which in turn induces the expression of proapoptotic genes, such as Caspase7 or TRAIL (tumor necrosis factor (ligand) superfamily, member 10). Gain of function of Hif-2alpha as well as ATF3 is sufficient to trigger cell death, whereas loss of function of both proteins drastically inhibits UV-induced apoptosis. Repression of Hif-2alpha strongly impairs ATF3-mediated death, providing evidences that Hif-2alpha is the major death effector of ATF3. In addition, Hif-1alpha, already known as a proapoptotic gene, upon UV irradiation, is not able to compensate for the lack of Hif-2alpha expression, thereby confirming the major contribution of Hif-2alpha in UV-mediated cell death. We further demonstrate that this cascade of gene activation depends on p38 and c-Jun N-terminal kinase (JNK) activity. Impairment of such a pathway is likely to contribute to oncogenesis by promoting survival of cells that could accumulate severe chromosomal alterations.

Published
2008
Full Text
View/download PDF

Catalog

Books, media, physical & digital resources
See catalog results