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1. EWSR1-PATZ1 gene fusion may define a new glioneuronal tumor entity

Author

Anne-Isabelle Bertozzi, Emmanuelle Uro-Coste, Claude-Alain Maurage, Sarah Péricart, Sergio Boetto, Yvan Nicaise, Sophie Le Guellec, Camille Franchet, Alix Delrieu, Matthieu Vinchon, David Grand, Frédéric Escudié, David T.W. Jones, Valérie Rigau, Anne Gomez-Brouchet, Aurore Siegfried, Jean-Christophe Sol, Audrey Rousseau, Franck-Emmanuel Roux, Dominique Figarella-Branger, Département de Pathologie [CHU Toulouse], CHU Toulouse [Toulouse], 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), Design and Application of Innovative Local Treatments in Glioblastoma (CRCINA-ÉQUIPE 17), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA), Département de Pathologie [CHU Angers], Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), Département de Pathologie [CHRU Lille], Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U1172 Inserm - U837 (JPArc), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Lille Nord de France (COMUE)-Université de Lille, Institut de pharmacologie et de biologie structurale (IPBS), Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Institut Claudius-Regaud [IUCT, Toulouse], Institut Universitaire du Cancer Toulouse - Oncopôle (IUCT), Département de Neurochirurgie [CHU Toulouse], Département de Neurochirurgie[Lille], Université de Lille, Droit et Santé-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Toulouse Neuro Imaging Center (ToNIC), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse]-CHU Toulouse [Toulouse], Département de Pathologie [Centre Médical Universitaire Montpellier], Centre Médical Universitaire Montpellier - CMUM, Institut des Neurosciences de Montpellier - Déficits sensoriels et moteurs (INM), Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM), Département d'Oncopédiatrie [CHU Toulouse], Hopp Children's Cancer Center Heidelberg [Heidelber, Germany] (KITZ), German Cancer Research Center - Deutsches Krebsforschungszentrum [Heidelberg] (DKFZ)-Heidelberg University Hospital [Heidelberg], Division of Pediatric Neurooncology [Heidelberg, Germany], German Cancer Research Center - Deutsches Krebsforschungszentrum [Heidelberg] (DKFZ)-German Cancer Consortium [Heidelberg] (DKTK), Département de Pathologie [CHU Marseille], CHU Marseille, Institut de neurophysiopathologie (INP), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), D. Jones is supported by funding for the Everest Centre for Paediatric Low- Grade Brain Tumour Research through the Brain Tumour Charity (UK). We are grateful to Karen Silva for her help in handling tumor samples from the different pathological departments. Samples from Marseille were retrieved from the AP-HM tumor bank AC 2017:1786. Samples from Toulouse were retrieved from the CHU de Toulouse tumor bank BB-0033-00014., Service Anatomie et cytologie pathologiques [CHU Toulouse], Pôle Biologie [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U837 (JPArc), Université Lille Nord de France (COMUE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), Institut Universitaire du Cancer de Toulouse - Oncopole (IUCT Oncopole - UMR 1037), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service Neurochirurgie [CHU Toulouse], Pôle Neurosciences [CHU Toulouse], Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Toulouse Mind & Brain Institut (TMBI), Université Toulouse - Jean Jaurès (UT2J)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Université Toulouse - Jean Jaurès (UT2J)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées, Institut des Neurosciences de Montpellier (INM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Sercice Hématologie, immunologie et oncologie pédiatrique [CHU Toulouse], Pôle Enfants [CHU Toulouse], Bernardo, Elizabeth, 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), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Toulouse Mind & Brain Institut (TMBI), Université Toulouse - Jean Jaurès (UT2J), Université de Toulouse (UT)-Université de Toulouse (UT)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université Toulouse - Jean Jaurès (UT2J), Université de Toulouse (UT)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT), Design and Application of Innovative Local Treatments in Glioblastoma (CRCINA - Département NOHMAD - Equipe 17), Centre de recherche de Cancérologie et d'Immunologie / Nantes - Angers (CRCINA), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Centre de recherche Jean-Pierre Aubert-Neurosciences et Cancer, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Droit et Santé, Institut pour la Recherche sur le Cancer de Lille (U837 INSERM - IRCL), Institut pour la recherche sur le cancer de Lille [Lille] (IRCL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre de Recherche Jean-Pierre AUBERT - Neurosciences et Cancer -JPArc [Lille], Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse]-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM), Hopp Children's Cancer Center at the NCT Heidelberg - KiTZ [Heidelber, Germany]g, Centre de Recherche en Cancérologie de Toulouse ( CRCT ), Université Paul Sabatier - Toulouse 3 ( UPS ) -CHU Toulouse [Toulouse]-Hôpital Purpan [Toulouse]-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Design and Application of Innovative Local Treatments in Glioblastoma ( CRCINA - Département NOHMAD - Equipe 17 ), Centre de recherche de Cancérologie et d'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 ) -Institut de Recherche en Santé de l'Université de Nantes ( IRS-UN ) -Centre hospitalier universitaire de Nantes ( CHU Nantes ) -Université d'Angers ( UA ) -Université de Nantes ( UN ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ) -Institut de Recherche en Santé de l'Université de Nantes ( IRS-UN ) -Centre hospitalier universitaire de Nantes ( CHU Nantes ), Centre hospitalier universitaire d'Angers ( CHU Angers ), Centre Hospitalier Régional Universitaire [Lille] ( CHRU Lille ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université de Lille, Droit et Santé, Institut pour la Recherche sur le Cancer de Lille ( U837 INSERM - IRCL ), Institut pour la recherche sur le cancer de Lille [Lille] ( IRCL ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre de Recherche Jean-Pierre AUBERT - Neurosciences et Cancer -JPArc [Lille], Institut de pharmacologie et de biologie structurale ( IPBS ), Université Paul Sabatier - Toulouse 3 ( UPS ) -Centre National de la Recherche Scientifique ( CNRS ), Institut Universitaire du Cancer Toulouse - Oncopôle ( IUCT ), Centre Hospitalier Universitaire de Toulouse - CHU Toulouse (FRANCE), Université de Lille, Droit et Santé-Centre Hospitalier Régional Universitaire [Lille] ( CHRU Lille ), Toulouse Neuro Imaging Center ( ToNIC ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Hôpital Purpan - Centre Hospitalier Universitaire (CHU) de Toulouse-Université Toulouse III - Paul Sabatier, Institut des Neurosciences de Montpellier - Déficits sensoriels et moteurs ( INM ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université de Montpellier ( UM ), German Cancer Research Center ( DKFZ ) -German Cancer Consortium - DKTK [Heidelberg, Germany], Institut de neurophysiopathologie ( INP ), and Aix Marseille Université ( AMU ) -Centre National de la Recherche Scientifique ( CNRS )

Subjects
0301 basic medicine, Adult, Male, DNA Copy Number Variations, Kruppel-Like Transcription Factors, Locus (genetics), [SDV.CAN]Life Sciences [q-bio]/Cancer, Biology, [ SDV.CAN ] Life Sciences [q-bio]/Cancer, Pathology and Forensic Medicine, Ganglioglioma, Fusion gene, 03 medical and health sciences, symbols.namesake, 0302 clinical medicine, [SDV.CAN] Life Sciences [q-bio]/Cancer, Glioma, medicine, Biomarkers, Tumor, Humans, Copy-number variation, Child, In Situ Hybridization, Fluorescence, Research Articles, Sanger sequencing, Brain Neoplasms, General Neuroscience, Methylation, DNA Methylation, medicine.disease, Neoplasms, Neuroepithelial, 3. Good health, Repressor Proteins, 030104 developmental biology, Fusion transcript, Cancer research, symbols, Female, Neurology (clinical), Gene Fusion, RNA-Binding Protein EWS, 030217 neurology & neurosurgery
Abstract

International audience; We investigated the challenging diagnostic case of a ventricular cystic glioneuronal tumor with papillary features, by RNA sequencing using the Illumina TruSight RNA Fusion panel. We did not retrieve the SLC44A1-PRKCA fusion gene specific for papillary glioneuronal tumor, but an EWSR1-PATZ1 fusion transcript. RT-PCR followed by Sanger sequencing confirmed the EWSR1-PATZ1 fusion. It matched with canonic EWSR1 fusion oncogene, juxtaposing the entire N terminal transcriptional activation domain of EWSR1 gene and the C terminal DNA binding domain of a transcription factor gene, PATZ1. PATZ1 protein belongs to the BTB-ZF (broad-complex, tramtrack and bric-à-brac -zinc finger) family. It directly regulates Pou5f1 and Nanog and is essential to maintaining stemness by inhibiting neural differentiation. EWSR1-PATZ1 fusion is a rare event in tumors: it was only reported in six round cell sarcomas and in three gliomas of three exclusively molecular studies. The first reported glioma was a BRAF[V600E] negative ganglioglioma, the second a BRAF[V600E] negative glioneuronal tumor, not otherwise specified, and the third, very recently reported, a high grade glioma, not otherwise specified. In our study, forty BRAF[V600E] negative gangliogliomas were screened by FISH using EWSR1 break-apart probes. We performed methylation profiling for the index case and for seven out of the ten FISH positive cases. The index case clustered apart from other pediatric low grade glioneuronal entities, and specifically from the well-defined ganglioglioma methylation group. An additional pediatric intraventricular ganglioglioma clustered slightly more closely with ganglioglioma, but showed differences from the main ganglioglioma group and similarities with the index case. Both cases harbored copy number variations at the PATZ1 locus. EWSR1-PATZ1 gene fusion might define a new type of glioneuronal tumors, distinct from gangliogliomas.

Published
2019
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2. Vaginal mucosal homeostatic response may determine pregnancy outcome in women with bacterial vaginosis a pilot study

Author

Emmanuel Faure, Bruno Grandbastien, Céline Villenet, Eric Kipnis, Martin Figeac, Teddy Grandjean, Sylvain Dubucquoi, Karine Faure, Rodrigue Dessein, Damien Subtil, Gilles Brabant, Recherche translationelle relations hôte-pathogènes, Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Plateforme de génomique fonctionnelle et structurelle [Lille], Institut pour la recherche sur le cancer de Lille [Lille] (IRCL)-Université de Lille, Droit et Santé, Lille Inflammation Research International Center - U 995 (LIRIC), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP), Institut pour la Recherche sur le Cancer de Lille (U837 INSERM - IRCL), Institut pour la recherche sur le cancer de Lille [Lille] (IRCL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre de Recherche Jean-Pierre AUBERT - Neurosciences et Cancer -JPArc [Lille], Université de Lille, Hôpital Saint Vincent de Paul de Lille, Groupe Hospitalier de l'Institut Catholique de Lille (GHICL), Evaluation des technologies de santé et des pratiques médicales - ULR 2694 (METRICS), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Institut pour la recherche sur le cancer de Lille [Lille] (IRCL)-Institut National de la Santé et de la Recherche Médicale (INSERM), Groupement des Hôpitaux de l'Institut Catholique de Lille (GHICL), Université catholique de Lille (UCL)-Université catholique de Lille (UCL), Université de Lille, LillOA, CHU Lille, Inserm, Recherche translationnelle : relations hôte-pathogènes - EA 7366, METRICS : Evaluation des technologies de santé et des pratiques médicales - ULR 2694, Lille Inflammation Research International Center - U 995 [LIRIC], Institut pour la Recherche sur le Cancer de Lille [U837 INSERM - IRCL], and Evaluation des technologies de santé et des pratiques médicales - ULR 2694 [METRICS]

Subjects
0301 basic medicine, MESH: Mucosal, [SDV]Life Sciences [q-bio], Physiology, 0302 clinical medicine, MESH: Pregnancy, Lactobacillus, MESH: Immunity, education.field_of_study, 030219 obstetrics & reproductive medicine, biology, General Medicine, [SDV] Life Sciences [q-bio], MESH: Infectious/immunology, MESH: Homeostasis, MESH: Pregnancy Complications, Anaerobic bacteria, Bacterial vaginosis, medicine.symptom, Population, Inflammation, MESH: Bacterial/immunology, 03 medical and health sciences, Immunity, MESH: Vaginosis, medicine, education, Pregnancy, MESH: Humans, business.industry, MESH: Adult, medicine.disease, biology.organism_classification, MESH: Pilot Projects, MESH: Pregnancy Outcome, 030104 developmental biology, Immunology, Nugent score, business, MESH: Female
Abstract

International audience; Bacterial vaginosis (BV) is considered as a trigger for an inflammatory response that could promote adverse pregnancy outcome (APO). We hypothesized that BV-related inflammation could be counterbalanced by anti-inflammatory and mucosal homeostatic responses that could participate in pregnancy outcomes.A total of 402 vaginal self-samples from pregnant women in their first trimester were screened by Nugent score. In this population, we enrolled 23 pregnant women with BV but without APO, 5 pregnant women with BV and developing APO, 21 pregnant women with intermediate flora, and 28 random control samples from pregnant women without BV or APO.BV without APO in pregnant women was associated with 28-fold interleukin-8, 5-fold interleukin-10, and 40-fold interleukin-22 increases in expression compared to controls. BV associated with APO in pregnant women shared 4-fold increase in tumor necrosis factor, 100-fold decrease in interleukin-10, and no variation in interleukin-22 expressions compared to controls. Next-generation sequencing of vaginal microbiota revealed a shift from obligate anaerobic bacteria dominance in BV without APO pregnant women to Lactobacillus dominance microbiota in BV with APO.Our results show that the anti-inflammatory and mucosal homeostatic responses to BV may determine outcome of pregnancy in the setting of BV possibly through effects on the vaginal microbiota.

Published
2016
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3. Frequency and Genomic Aspects of Intrinsic Resistance to Vismodegib in Locally Advanced Basal Cell Carcinoma

Author

Andrey A. Yurchenko, Oltin T. Pop, Meriem Ighilahriz, Ismael Padioleau, Fatemeh Rajabi, Hayley J. Sharpe, Nicolas Poulalhon, Brigitte Dreno, Amir Khammari, Marc Delord, Antonio Alberti, Nadem Soufir, Maxime Battistella, Samia Mourah, Fanny Bouquet, Ariel Savina, Andrej Besse, Max Mendez-Lopez, Florent Grange, Sandrine Monestier, Laurent Mortier, Nicolas Meyer, Caroline Dutriaux, Caroline Robert, Philippe Saiag, Florian Herms, Jerome Lambert, Frederic J. de Sauvage, Nicolas Dumaz, Lukas Flatz, Nicole Basset-Seguin, Sergey I. Nikolaev, Pecqueret, Valérie, Biomarqueurs prédictifs et nouvelles stratégies moléculaires en thérapeutique anticancéreuse (U981), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Prédicteurs moléculaires et nouvelles cibles en oncologie (PMNCO), Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Brustzentrum Kantonsspital St. Gallen, Immunologie humaine, physiopathologie & immunothérapie (HIPI (UMR_S_976 / U976)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), The Babraham Institute [Cambridge, UK], Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL), 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), Centre d’Investigation Clinique de Nantes (CIC Nantes), Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre hospitalier universitaire de Nantes (CHU Nantes), Immunology and New Concepts in ImmunoTherapy (INCIT), Université d'Angers (UA)-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)-Nantes Université - UFR de Médecine et des Techniques Médicales (Nantes Univ - UFR MEDECINE), Centre hospitalier universitaire de Nantes (CHU Nantes), Université Paris Diderot, Sorbonne Paris Cité, Paris, France, Université Paris Diderot - Paris 7 (UPD7), Institut de Recherche Saint-Louis - Hématologie Immunologie Oncologie (Département de recherche de l’UFR de médecine, ex- Institut Universitaire Hématologie-IUH) (IRSL), Université Paris Cité (UPCité), Hopital Saint-Louis [AP-HP] (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut ROCHE [Boulogne-Billancourt], Roche S.A.S, Centre Hospitalier Universitaire de Reims (CHU Reims), Hôpital de la Timone [CHU - APHM] (TIMONE), Equipe 3 - Facteurs de persistance des cellules leucémique - (INSERM U837), Institut pour la Recherche sur le Cancer de Lille (U837 INSERM - IRCL), Institut pour la recherche sur le cancer de Lille [Lille] (IRCL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut pour la recherche sur le cancer de Lille [Lille] (IRCL)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), CHU Bordeaux [Bordeaux], Institut Gustave Roussy (IGR), Oncologie dermatologique, Département de médecine oncologique [Gustave Roussy], Institut Gustave Roussy (IGR)-Institut Gustave Roussy (IGR), Hôpital Ambroise Paré [AP-HP], Service de Dermatologie [AP-HP Hôpital Saint-Louis], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Genentech, Inc., and Genentech, Inc. [San Francisco]

Subjects
Cancer Research, Skin Neoplasms, animal structures, integumentary system, Pyridines, [SDV]Life Sciences [q-bio], fungi, Antineoplastic Agents, [SDV.CAN]Life Sciences [q-bio]/Cancer, [SDV] Life Sciences [q-bio], [SDV.CAN] Life Sciences [q-bio]/Cancer, Oncology, Carcinoma, Basal Cell, Humans, Anilides, Hedgehog Proteins, Cerebellar Neoplasms
Abstract

Purpose: Vismodegib is approved for the treatment of locally advanced basal cell carcinoma (laBCC), but some cases demonstrate intrinsic resistance (IR) to the drug. We sought to assess the frequency of IR to vismodegib in laBCC and its underlying genomic mechanisms. Experimental Design: Response to vismodegib was evaluated in a cohort of 148 laBCC patients. Comprehensive genomic and transcriptomic profiling was performed in a subset of five intrinsically resistant BCC (IR-BCC). Results: We identified that IR-BCC represents 6.1% of laBCC in the studied cohort. Prior treatment with chemotherapy was associated with IR. Genetic events that were previously associated with acquired resistance (AR) in BCC or medulloblastoma were observed in three out of five IR-BCC. However, IR-BCCs were distinct by highly rearranged polyploid genomes. Functional analyses identified hyperactivation of the HIPPO-YAP and WNT pathways at RNA and protein levels in IR-BCC. In vitro assay on the BCC cell line further confirmed that YAP1 overexpression increases the cell proliferation rate. Conclusions: IR to vismodegib is a rare event in laBCC. IR-BCCs frequently harbor resistance mutations in the Hh pathway, but also are characterized by hyperactivation of the HIPPO-YAP and WNT pathways.

Published
2022
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4. MUC1-C nuclear localization drives invasiveness of renal cancer cells through a sheddase/gamma secretase dependent pathway

Author

Nicolas Sergeant, Brigitte Hémon, Nicolas Pottier, Viviane Gnemmi, Xavier Leroy, Bélinda Ringot, Sébastien Aubert, Audrey Bouillez, François Glowacki, Kelly Gaudelot, Malika Hamdane, Christelle Cauffiez, Isabelle Van Seuningen, Caroline Butruille, Michael Perrais, Institut pour la Recherche sur le Cancer de Lille (U837 INSERM - IRCL), Institut pour la recherche sur le cancer de Lille [Lille] (IRCL)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Lille, Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Impact de l'environnement chimique sur la santé humaine - ULR 4483 (IMPECS), Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Institut pour la recherche sur le cancer de Lille [Lille] (IRCL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre de Recherche Jean-Pierre AUBERT - Neurosciences et Cancer -JPArc [Lille], VAN SEUNINGEN, ISABELLE, Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U1172 Inserm - U837 (JPArc), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Lille Nord de France (COMUE)-Université de Lille, Pôle de Biologie Pathologie Génétique [CHU Lille], Mucines Epitheliales : du Gene a la Fonction, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Droit et Santé, Université des Sciences et Technologies (Lille 1) (USTL), Neuroendocrinologie et physiopathologie neuronale, Alzheimer & Tauopathies (Equipe 1), Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U1172 Inserm - U837 (JPArc), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Lille Nord de France (COMUE)-Université de Lille-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Lille Nord de France (COMUE)-Université de Lille, UMR837, Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de Nanotechnologie et d'Instrumentation Optique (LNIO), Institut Charles Delaunay (ICD), Université de Technologie de Troyes (UTT)-Centre National de la Recherche Scientifique (CNRS)-Université de Technologie de Troyes (UTT)-Centre National de la Recherche Scientifique (CNRS), Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U837 (JPArc), Université Lille Nord de France (COMUE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Université de Lille, Sciences et Technologies, Alzheimer & Tauopathies [JPArc], Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U837 (JPArc), Université Lille Nord de France (COMUE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Université Lille Nord de France (COMUE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Institut pour la Recherche sur le Cancer de Lille [U837 INSERM - IRCL], Centre Hospitalier Régional Universitaire [Lille] [CHRU Lille], and Impact de l'environnement chimique sur la santé humaine - ULR 4483 [IMPECS]

Subjects
ADAM10, [SDV]Life Sciences [q-bio], Mice, SCID, γ-secretase, Metastasis, Mice, 0302 clinical medicine, Anoikis, skin and connective tissue diseases, ComputingMilieux_MISCELLANEOUS, 0303 health sciences, ADAM17, kidney cancer, invasion, Kidney Neoplasms, Cell aggregation, 3. Good health, [SDV] Life Sciences [q-bio], Oncology, 030220 oncology & carcinogenesis, Disease Progression, Heterografts, Signal Transduction, Research Paper, [SDV.CAN]Life Sciences [q-bio]/Cancer, MUC1, Biology, Transfection, digestive system, 03 medical and health sciences, [SDV.CAN] Life Sciences [q-bio]/Cancer, Cell Line, Tumor, medicine, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Animals, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, neoplasms, Gamma secretase, 030304 developmental biology, Cell Nucleus, Mucin-1, Sheddase, medicine.disease, biological factors, digestive system diseases, Protein Subunits, Tumor progression, Cancer cell, Cancer research, Amyloid Precursor Protein Secretases
Abstract

International audience; MUC1 is a membrane-anchored mucin and its cytoplasmic tail (CT) can interact with many signaling pathways and act as a co-transcription factor to activate genes involved in tumor progression and metastasis. MUC1 is overexpressed in renal cell carcinoma with correlation to prognosis and has been implicated in the hypoxic pathway, the main renal carcinogenetic pathway. In this context, we assessed the effects of MUC1 overexpression on renal cancer cells properties. Using shRNA strategy and/or different MUC1 constructs, we found that MUC1-extracellular domain and MUC1-CT are involved in increase of migration, cell viability, resistance to anoikis and in decrease of cell aggregation in cancer cells. Invasiveness depends only on MUC1-CT. Then, by using siRNA strategy and/or pharmacological inhibitors or peptides, we showed that sheddases ADAM10, ADAM17 and gamma-secretase are necessary for MUC1 C-terminal subunit (MUC1-C) nuclear location and in increase of invasion property. Finally, MUC1 overexpression increases ADAM10/17 protein expression suggesting a positive regulatory loop. In conclusion, we report that MUC1 acts in renal cancer progression and MUC1-C nuclear localization drives invasiveness of cancer cells through a sheddase/gamma secretase dependent pathway. MUC1 appears as a therapeutic target by blocking MUC1 cleavage or nuclear translocation by using pharmacological approach and peptide strategies.

Published
2014
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5. Mucin 16 (cancer antigen 125) expression in human tissues and cell lines and correlation with clinical outcome in adenocarcinomas of the pancreas, esophagus, stomach, and colon

Author

Elizabeth A. Montgomery, Anirban Maitra, Michael Goggins, Audrey Vincent, Radha Mukherjee, Shih Hsun Chen, Mirte M. Streppel, Nathaniel R. Campbell, Konstantinos Konstantopoulos, Isabelle Van Seuningen, Johns Hopkins University (JHU), University Medical Center [Utrecht], Institut pour la Recherche sur le Cancer de Lille (U837 INSERM - IRCL), Institut pour la recherche sur le cancer de Lille [Lille] (IRCL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre de Recherche Jean-Pierre AUBERT - Neurosciences et Cancer -JPArc [Lille], Université de Lille, Institut pour la recherche sur le cancer de Lille [Lille] (IRCL)-Institut National de la Santé et de la Recherche Médicale (INSERM), VAN SEUNINGEN, ISABELLE, Johns Hopkins University [JHU], and Institut pour la Recherche sur le Cancer de Lille [U837 INSERM - IRCL]

Subjects
Male, medicine.medical_specialty, Esophageal Neoplasms, [SDV]Life Sciences [q-bio], Blotting, Western, Kaplan-Meier Estimate, Adenocarcinoma, Digestive System Neoplasms, Gastroenterology, Article, Pathology and Forensic Medicine, 03 medical and health sciences, 0302 clinical medicine, Stomach Neoplasms, Cell Line, Tumor, Internal medicine, Biomarkers, Tumor, Humans, Medicine, Lymph node, ComputingMilieux_MISCELLANEOUS, Aged, Neoplasm Staging, 030304 developmental biology, 0303 health sciences, Tissue microarray, business.industry, Mucin, Membrane Proteins, Middle Aged, Prognosis, medicine.disease, Immunohistochemistry, digestive system diseases, 3. Good health, Pancreatic Neoplasms, [SDV] Life Sciences [q-bio], medicine.anatomical_structure, CA-125 Antigen, 030220 oncology & carcinogenesis, Colonic Neoplasms, Cancer cell, Cancer research, Female, business, Pancreas, Ovarian cancer
Abstract

Mucin 16 (cancer antigen 125) is a cell surface glycoprotein that plays a role in promoting cancer cell growth in ovarian cancer. The aims of this study were to examine mucin 16 expression in a large number of digestive tract adenocarcinomas and precursors and to determine whether mucin 16 up-regulation is correlated with patient outcome. Tissue microarrays were constructed using surgical resection tissues and included pancreatic (115 normal, 29 precursors, 200 pancreatic ductal adenocarcinomas), esophageal (86 normal, 104 precursors, 95 esophageal adenocarcinomas, 35 lymph node metastases), gastric (211 normal, 8 precursors, 119 gastric adenocarcinomas, 62 lymph node metastases), and colorectal (34 normal, 17 precursors, 39 colorectal adenocarcinomas) tissues. Mucin 16 was detected in 81.5%, 69.9%, 41.2%, and 64.1% of the pancreatic ductal adenocarcinomas, esophageal adenocarcinomas, gastric adenocarcinomas, and colorectal adenocarcinomas, respectively. Mucin 16 was seen in a subset of the precursors. On multivariate analysis, moderate/diffuse mucin 16 in pancreatic ductal adenocarcinomas was strongly associated with poor survival (P < .001), independent of other prognosis predictors. A similar trend was observed for esophageal adenocarcinomas (P = .160) and gastric adenocarcinomas (P = .080). Focal mucin 16 in colorectal adenocarcinomas was significantly correlated (P = .044) with a better patient outcome, when compared with mucin 16–negative cases. Using Western blot analysis, we found mucin 16 expression in 3 of 6 pancreatic ductal adenocarcinoma and 1 of 2 esophageal adenocarcinoma cell lines. We conclude that most of the digestive tract adenocarcinomas and a subset of their precursors express mucin 16. Mucin 16 expression is an independent predictor of poor outcome in pancreatic ductal adenocarcinomas and potentially in esophageal adenocarcinomas and gastric adenocarcinomas. We propose that mucin 16 may function as a prognostic marker and therapeutic target in the future.

Published
2012
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6. Alzheimer PHF-tau aggregates do not spread tau pathology to the brain via the Retino-tectal projection after intraocular injection in male mouse models

Author

M.-A. de Fisenne, Z. Yilmaz, R. De Decker, V. Suain, L. Buée, K. Ando, J.-P. Brion, K. Leroy, ULB Neuroscience Institute [Brussels] (UNI), Université libre de Bruxelles (ULB), Institut pour la Recherche sur le Cancer de Lille (U837 INSERM - IRCL), Institut pour la recherche sur le cancer de Lille [Lille] (IRCL)-Institut National de la Santé et de la Recherche Médicale (INSERM), and BUEE, Luc

Subjects
Male, Retinal Ganglion Cells, Prions, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, [SDV.NEU.NB] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Brain, tau Proteins, Neurofibrillary Tangles, Mice, Transgenic, Alzheimer's disease, Retina, Mice, Disease Models, Animal, Neurology, Transgenic mouse, Alzheimer Disease, Tau pathology propagation, Animals, Humans, Intraocular injection, Injections, Intraocular
Abstract

International audience; Neurofibrillary tangles (NFT), a neuronal lesion found in Alzheimer's disease (AD), are composed of fibrillary aggregates of modified forms of tau proteins. The propagation of NFT follows neuroanatomical pathways suggesting that synaptically connected neurons could transmit tau pathology by the recruitment of normal tau in a prion-like manner. Moreover, the intracerebral injection of pathological tau from AD brains induces the seeding of normal tau in mouse brain. Creutzfeldt-Jacob disease has been transmitted after ocular transplants of cornea or sclera and the scrapie agent can spread across the retino-tectal pathway after intraocular injection of scrapie mouse brain homogenates. In AD, a tau pathology has been detected in the retina. To investigate the potential risk of tau pathology transmission during eye surgery using AD tissue material, we have analysed the development of tau pathology in the visual pathway of mice models expressing murine tau, wild-type or mutant human tau after intraocular injection of pathological tau proteins from AD brains. Although these pathological tau proteins were internalized in retinal ganglion cells, they did not induce aggregation of endogenous tau nor propagation of a tau pathology in the retino-tectal pathway after a 6-month incubation period. These results suggest that retinal ganglion cells exhibit a resistance to develop a tau pathology, and that eye surgery is not a major iatrogenic risk of transmission of tau pathology, contrary to what has been observed for transmission of infectious prions in prion diseases.

Published
2022
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7. Pathogenic variants in IMPG1 cause autosomal dominant and autosomal recessive retinitis pigmentosa

Author

Guylène Le Meur, Susanne Roosing, Panagiotis I. Sergouniotis, Marta Corton, Sandro Banfi, Graeme C.M. Black, Ivan Conte, Hélène Naacke, Carmen Ayuso, Christian Hamel, Almudena Avila-Fernandez, Agnès Muller, Guillaume Olivier, Daniela Intartaglia, Claire-Marie Dhaenens, Gaël Manes, Sanne K Verbakel, Jeroen Klevering, Isabelle Meunier, Béatrice Bocquet, Carel B. Hoyng, Agathe Roubertie, Audrey Sénéchal, Xavier Zanlonghi, Institut des Neurosciences de Montpellier (INM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Universidad Autónoma de Madrid (UAM), CIBER de Enfermedades Raras (CIBERER), Università degli studi della Campania 'Luigi Vanvitelli' = University of the Study of Campania Luigi Vanvitelli, Radboud University Medical Center [Nijmegen], Manchester Academic Health Science Centre (MAHSC), University of Manchester [Manchester], Centre hospitalier universitaire de Nantes (CHU Nantes), Equipe 3 - Facteurs de persistance des cellules leucémique - (INSERM U837), Institut pour la Recherche sur le Cancer de Lille (U837 INSERM - IRCL), Institut pour la recherche sur le cancer de Lille [Lille] (IRCL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut pour la recherche sur le cancer de Lille [Lille] (IRCL)-Institut National de la Santé et de la Recherche Médicale (INSERM), Lille Neurosciences & Cognition - U 1172 (LilNCog), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Clinique Saint-Joseph Angoulême (CSJA), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Hôpital Gui de Chauliac [CHU Montpellier], University of Naples Federico II = Università degli studi di Napoli Federico II, Clinique Jules-Vernes [Nantes], Hôpital Gui de Chauliac [Montpellier], Michel-Avella, Amandine, Olivier, Guillaume, Corton, Marta, Intartaglia, Daniela, Verbakel, Sanne K, Sergouniotis, Panagiotis I, Le Meur, Guylène, Dhaenens, Claire-Marie, Naacke, Hélène, Avila-Fernández, Almudena, Hoyng, Carel B, Klevering, Jeroen, Bocquet, Béatrice, Roubertie, Agathe, Sénéchal, Audrey, Banfi, Sandro, Muller, Agnè, Hamel, Christian L, Black, Graeme C, Conte, Ivan, Roosing, Susanne, Zanlonghi, Xavier, Ayuso, Carmen, Meunier, Isabelle, and Manes, Gaël

Subjects
0301 basic medicine, MESH: Extracellular Matrix Proteins, sequence analysis, [SDV]Life Sciences [q-bio], eye disease, Sensory disorders Donders Center for Medical Neuroscience [Radboudumc 12], 0302 clinical medicine, Benign concentric annular macular dystrophy, MESH: Eye Proteins, Missense mutation, genetics, Genetics (clinical), Exome sequencing, Genetics, MESH: Aged, MESH: Exome, MESH: Middle Aged, medicine.diagnostic_test, MESH: Retina, MESH: Genetic Predisposition to Disease, [SDV] Life Sciences [q-bio], MESH: Proteoglycans, MESH: Mutation, Sequence analysis, MESH: Pedigree, MESH: Arthrogryposis, Vitelliform macular dystrophy, Biology, MESH: Phenotype, 03 medical and health sciences, All institutes and research themes of the Radboud University Medical Center, MESH: Whole Exome Sequencing, Retinitis pigmentosa, medicine, MESH: Macular Degeneration, MESH: Genes, Recessive, Genetic testing, MESH: Humans, Genetic heterogeneity, eye diseases, MESH: Retrospective Studies, medicine.disease, MESH: Male, ophthalmology, 030104 developmental biology, 030221 ophthalmology & optometry, MESH: Retinitis Pigmentosa, genetic, MESH: Inheritance Patterns, MESH: Female
Abstract

BackgroundInherited retinal disorders are a clinically and genetically heterogeneous group of conditions and a major cause of visual impairment. Common disease subtypes include vitelliform macular dystrophy (VMD) and retinitis pigmentosa (RP). Despite the identification of over 90 genes associated with RP, conventional genetic testing fails to detect a molecular diagnosis in about one third of patients with RP.MethodsExome sequencing was carried out for identifying the disease-causing gene in a family with autosomal dominant RP. Gene panel testing and exome sequencing were performed in 596 RP and VMD families to identified additional IMPG1 variants. In vivo analysis in the medaka fish system by knockdown assays was performed to screen IMPG1 possible pathogenic role.ResultsExome sequencing of a family with RP revealed a splice variant in IMPG1. Subsequently, the same variant was identified in individuals from two families with either RP or VMD. A retrospective study of patients with RP or VMD revealed eight additional families with different missense or nonsense variants in IMPG1. In addition, the clinical diagnosis of the IMPG1 retinopathy-associated variant, originally described as benign concentric annular macular dystrophy, was also revised to RP with early macular involvement. Using morpholino-mediated ablation of Impg1 and its paralog Impg2 in medaka fish, we confirmed a phenotype consistent with that observed in the families, including a decreased length of rod and cone photoreceptor outer segments.ConclusionThis study discusses a previously unreported association between monoallelic or biallelic IMPG1 variants and RP. Notably, similar observations have been reported for IMPG2.

Published
2021
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8. Air pollution-derived PM2.5 impairs mitochondrial function in healthy and chronic obstructive pulmonary diseased human bronchial epithelial cells

Author

J.-M. Lo Guidice, Anne Loyens, Jerome Kluza, Esperanza Perdrix, Patrice Coddeville, Jules Sotty, Laurent Y. Alleman, Guillaume Garçon, Philippe Marchetti, Sébastien Anthérieu, Bérénice Leclercq, Institut pour la Recherche sur le Cancer de Lille (U837 INSERM - IRCL), Institut pour la recherche sur le cancer de Lille [Lille] (IRCL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre de Recherche Jean-Pierre AUBERT - Neurosciences et Cancer -JPArc [Lille], Département Sciences de l'Atmosphère et Génie de l'Environnement (SAGE), École des Mines de Douai (Mines Douai EMD), Institut Mines-Télécom [Paris] (IMT)-Institut Mines-Télécom [Paris] (IMT), Génie Civil et Environnemental (GCE), Centre for Energy and Environment (CERI EE), Ecole nationale supérieure Mines-Télécom Lille Douai (IMT Lille Douai), and Centre for Materials and Processes (CERI MP)

Subjects
0301 basic medicine, Mitochondrial ROS, Chemistry, Health, Toxicology and Mutagenesis, Cell, General Medicine, Oxidative phosphorylation, respiratory system, 010501 environmental sciences, Toxicology, 01 natural sciences, Pollution, Cell biology, 03 medical and health sciences, Cytosol, 030104 developmental biology, medicine.anatomical_structure, Apoptosis, [SDV.TOX]Life Sciences [q-bio]/Toxicology, medicine, Cytokine secretion, Signal transduction, ComputingMilieux_MISCELLANEOUS, Homeostasis, 0105 earth and related environmental sciences
Abstract

In order to clarify whether the mitochondrial dysfunction is closely related to the cell homeostasis maintenance after particulate matter (PM2.5) exposure, oxidative, inflammatory, apoptotic and mitochondrial endpoints were carefully studied in human bronchial epithelial BEAS-2B, normal human bronchial epithelial (NHBE) and chronic obstructive pulmonary disease (COPD)-diseased human bronchial epithelial (DHBE) cells acutely or repeatedly exposed to air pollution-derived PM2.5. Some modifications of the mitochondrial morphology were observed within all these cell models repeatedly exposed to the highest dose of PM2.5. Dose- and exposure-dependent oxidative damages were reported in BEAS-2B, NHBE and particularly COPD-DHBE cells acutely or repeatedly exposed to PM2.5. Nuclear factor erythroid 2-p45 related factor 2 (NRF2) gene expression and binding activity, together with the mRNA levels of some NRF2 target genes, were directly related to the number of exposures for the lowest PM2.5 dose (i.e., 2 μg/cm2), but, surprisingly, inversely related to the number of exposures for the highest dose (i.e., 10 μg/cm2). There were dose- and exposure-dependent increases of both nuclear factor kappa-B (NF-κB) binding activity and NF-κB target cytokine secretion in BEAS-2B, NHBE and particularly COPD-DHBE cells exposed to PM2.5. Mitochondrial ROS production, membrane potential depolarization, oxidative phosphorylation, and ATP production were significantly altered in all the cell models repeatedly exposed to the highest dose of PM2.5. Collectively, our results indicate a cytosolic ROS overproduction, inducing oxidative damage and activating oxygen sensitive NRF2 and NF-kB signaling pathways for all the cell models acutely or repeatedly exposed to PM2.5. However, one of the important highlight of our findings is that the prolonged and repeated exposure in BEAS-2B, NHBE and in particular sensible COPD-DHBE cells further caused an oxidative boost able to partially inactivate the NRF2 signaling pathway and to critically impair mitochondrial redox homeostasis, thereby producing a persistent mitochondrial dysfunction and a lowering cell energy supply.

Published
2018
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9. N-homocysteinylation of tau and MAP1 is increased in autopsy specimens of Alzheimer's disease and vascular dementia

Author

Rémy Umoret, Jeffrey M. Sequeira, Edward V. Quadros, Jean-Louis Guéant, Jean-Michel Camadro, Valérie Rigau, Sylvain Lehmann, Carine Bossenmeyer-Pourié, Bernard Sablonnière, A. David Smith, Déborah Helle, Jean-Luc Daval, Racha Kerek, Rosa-Maria Guéant-Rodriguez, Vincent Deramecourt, Audrey Gabelle, Grégory Pourié, Nutrition-Génétique et Exposition aux Risques Environnementaux (NGERE), Université de Lorraine (UL)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de génétique humaine (IGH), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Centre de Biologie-Pathologie, UF de Neurobiologie-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Institut Jacques Monod (IJM (UMR_7592)), Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Service de Biopathologie [CHRU Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), SUNY Downstate Medical Center, State University of New York (SUNY), IMPACT GEENAGE, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), University of Oxford [Oxford], Cellules Souches, Plasticité Cellulaire, Médecine Régénératrice et Immunothérapies (IRMB), Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Institut pour la Recherche sur le Cancer de Lille (U837 INSERM - IRCL), and Institut pour la recherche sur le cancer de Lille [Lille] (IRCL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre de Recherche Jean-Pierre AUBERT - Neurosciences et Cancer -JPArc [Lille]

Subjects
0301 basic medicine, medicine.medical_specialty, Hyperhomocysteinemia, Aging, Homocysteine, Normal diet, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Hippocampus, tau Proteins, folate, Pathology and Forensic Medicine, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Alzheimer Disease, Internal medicine, medicine, Animals, Humans, Cognitive Dysfunction, Vitamin B12, tau, Cognitive decline, Vascular dementia, Mice, Knockout, Alzheimer-type dementia, business.industry, Dementia, Vascular, microtubule-associated proteins, Brain, homocysteine, vitamin B12, medicine.disease, 3. Good health, Rats, 030104 developmental biology, Endocrinology, chemistry, Ageing, 030220 oncology & carcinogenesis, Female, Autopsy, business
Abstract

International audience; The pathomechanisms that associate a deficit in folate and/or vitamin B12 and the subsequent hyperhomocysteinemia with pathological brain ageing are unclear. We investigated the homocysteinylation of microtubule-associated proteins (MAPs) in brains of patients with Alzheimer's disease or vascular dementia, and in rats depleted in folate and vitamin B12, Cd320 KO mice with selective B12 brain deficiency and H19-7 neuroprogenitors lacking folate. Compared with controls, N-homocysteinylated tau and MAP1 were increased and accumulated in protein aggregates and tangles in the cortex, hippocampus and cerebellum of patients and animals. N-homocysteinylation dissociated tau and MAPs from β-tubulin, and MS analysis showed that it targets lysine residues critical for their binding to β-tubulin. N-homocysteinylation increased in rats exposed to vitamin B12 and folate deficit during gestation and lactation and remained significantly higher when they became 450 days-old, despite returning to normal diet at weaning, compared with controls. It was correlated with plasma homocysteine (Hcy) and brain expression of methionine tRNAsynthetase (MARS), the enzyme required for the synthesis of Hcy-thiolactone, the substrate of N-homocysteinylation. Experimental inactivation of MARS prevented the N-homocysteinylation of tau and MAP1, and the dissociation of tau and MAP1 from β-tubulin and PSD95 in cultured neuroprogenitors. In conclusion, increased N-homocysteinylation of tau and MAP1 is a mechanism of brain ageing that depends on Hcy concentration and expression of MARS enzyme. Its irreversibility and cumulative occurrence throughout life may explain why B12 and folate supplementation of the elderly has limited effects, if any, to prevent pathological brain ageing and cognitive decline. Copyright © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Published
2018
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10. Hypothalamic Tanycytes Are an ERK-Gated Conduit for Leptin into the Brain

Author

Sowmyalakshmi Rasika, Eric Trinquet, Eglantine Balland, Sebastien G. Bouret, Bénédicte Dehouck, Emilie Caron, Ralf Jockers, Julie Dam, Andrea Messina, Youssef Anouar, Sophie M. Steculorum, Fanny Langlet, Anthony Falluel-Morel, Vincent Prevot, Institut pour la Recherche sur le Cancer de Lille (U837 INSERM - IRCL), Institut pour la recherche sur le cancer de Lille [Lille] (IRCL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre de Recherche Jean-Pierre AUBERT - Neurosciences et Cancer -JPArc [Lille], Institut Cochin (IC UM3 (UMR 8104 / U1016)), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), 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), Cisbio Bioassays [Codolet, France] (Innovation Management / CbB), The Saban Research Institute [Los Angeles, CA, États-Unis], Children’s Hospital Los Angeles [Los Angeles]-University of Southern California (USC), Institut pour la recherche sur le cancer de Lille [Lille] (IRCL)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), University of Southern California (USC)-Children’s Hospital Los Angeles [Los Angeles], and Prevot, Vincent

Subjects
Leptin, Male, MAPK/ERK pathway, medicine.medical_specialty, Physiology, Blotting, Western, Ependymoglial Cells, Hypothalamus, Biology, Article, Mice, Internal medicine, medicine, Animals, Immunoprecipitation, Premovement neuronal activity, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Receptor, Molecular Biology, 2. Zero hunger, Leptin receptor, Tanycyte, digestive, oral, and skin physiology, Brain, Cell Biology, Mice, Inbred C57BL, medicine.anatomical_structure, Endocrinology, Median eminence, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Neuron, hormones, hormone substitutes, and hormone antagonists, Signal Transduction
Abstract

International audience; Leptin secreted by adipocytes acts on the brain to reduce food intake by regulating neuronal activity in the mediobasal hypothalamus (MBH). Obesity is associated with resistance to high circulating leptin levels. Here, we demonstrate that peripherally administered leptin activates its receptor (LepR) in median eminence tanycytes followed by MBH neurons, a process requiring tanycytic ERK signaling and the passage of leptin through the cerebrospinal fluid. In mice lacking the signal-transducing LepRb isoform or with diet-induced obesity, leptin taken up by tanycytes accumulates in the median eminence and fails to reach the MBH. Triggering ERK signaling in tanycytes with EGF reestablishes leptin transport, elicits MBH neuron activation and energy expenditure in obese animals, and accelerates the restoration of leptin sensitivity upon the return to a normal-fat diet. ERK-dependent leptin transport by tanycytes could thus play a critical role in the pathophysiology of leptin resistance, and holds therapeutic potential for treating obesity.

Published
2014
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11. Tanycytic VEGF-A Boosts Blood-Hypothalamus Barrier Plasticity and Access of Metabolic Signals to the Arcuate Nucleus in Response to Fasting

Author

Sebastien G. Bouret, Peter Carmeliet, Danièle Mazur, Andrea Messina, Vincent Prevot, Eglantine Balland, Serge Luquet, Ambrose A. Dunn-Meynell, Amélie Lacombe, Bénédicte Dehouck, Fanny Langlet, Massimiliano Mazzone, Barry E. Levin, Institut pour la Recherche sur le Cancer de Lille (U837 INSERM - IRCL), Institut pour la recherche sur le cancer de Lille [Lille] (IRCL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre de Recherche Jean-Pierre AUBERT - Neurosciences et Cancer -JPArc [Lille], Institut de médecine predictive et de recherche thérapeutique (IMPRT), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Centre Régional de Lutte contre le Cancer Oscar Lambret [Lille] (UNICANCER/Lille), Université Lille Nord de France (COMUE)-UNICANCER-Université Lille Nord de France (COMUE)-UNICANCER-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Droit et Santé-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Veterans Affairs Medical Center, Rutgers New Jersey Medical School (NJMS), Rutgers University System (Rutgers), Unité de Biologie Fonctionnelle et Adaptative (BFA (UMR_8251 / U1133)), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), VIB Vesalius Research Center (VRC), Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven), The Saban Research Institute [Los Angeles, CA, États-Unis], Children’s Hospital Los Angeles [Los Angeles]-University of Southern California (USC), Université d'Artois (UA), Prevot, Vincent, Institut pour la recherche sur le cancer de Lille [Lille] (IRCL)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Lille-UNICANCER-Université de Lille-UNICANCER-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Droit et Santé-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), and University of Southern California (USC)-Children’s Hospital Los Angeles [Los Angeles]

Subjects
Male, Vascular Endothelial Growth Factor A, medicine.medical_specialty, Animals, Arcuate Nucleus of Hypothalamus, Blood-Brain Barrier, Deoxyglucose, Ependyma, Fasting, Mice, Mice, Inbred C57BL, Signal Transduction, Tight Junctions, Endothelium, Physiology, Biology, Inbred C57BL, Energy homeostasis, 03 medical and health sciences, 0302 clinical medicine, Arcuate nucleus, Internal medicine, medicine, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Molecular Biology, 030304 developmental biology, 0303 health sciences, Tight junction, Tanycyte, Cell Biology, Endocrinology, medicine.anatomical_structure, Hypothalamus, Median eminence, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Signal transduction, 030217 neurology & neurosurgery
Abstract

International audience; The delivery of blood-borne molecules conveying metabolic information to neural networks that regulate energy homeostasis is restricted by brain barriers. The fenestrated endothelium of median eminence microvessels and tight junctions between tanycytes together compose one of these. Here, we show that the decrease in blood glucose levels during fasting alters the structural organization of this blood-hypothalamus barrier, resulting in the improved access of metabolic substrates to the arcuate nucleus. These changes are mimicked by 2-deoxyglucose-induced glucoprivation and reversed by raising blood glucose levels after fasting. Furthermore, we show that VEGF-A expression in tanycytes modulates these barrier properties. The neutralization of VEGF signaling blocks fasting-induced barrier remodeling and significantly impairs the physiological response to refeeding. These results implicate glucose in the control of blood-hypothalamus exchanges through a VEGF-dependent mechanism and demonstrate a hitherto unappreciated role for tanycytes and the permeable microvessels associated with them in the adaptive metabolic response to fasting.

Published
2013
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12. New selective carbonic anhydrase IX inhibitors: Synthesis and pharmacological evaluation of diarylpyrazole-benzenesulfonamides

Author

Samuel Meignan, Abigaëlle Gros, Tiphaine Rogez-Florent, Amélie Lansiaux, Catherine Foulon, Jean François Goossens, Raphaël Frédérick, Sebastien Gluszok, Bernard Masereel, Laurence Goossens, Perrine Six, Claudiu T. Supuran, Christine Bal-Mahieu, Andrea Scozzafava, Patrick Depreux, UCL - SSS/LDRI - Louvain Drug Research Institute, Groupe de Recherche Interdiscipinaire Innovation et Optimisation Thérapeutique - EA 4481 (GRIIOT), Université de Lille, Droit et Santé, Institut pour la Recherche sur le Cancer de Lille (U837 INSERM - IRCL), Institut pour la recherche sur le cancer de Lille [Lille] (IRCL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre de Recherche Jean-Pierre AUBERT - Neurosciences et Cancer -JPArc [Lille], Institut de Chimie Pharmaceutique Albert Lespagnol (ICPAL), Laboratorio di Chimica Bioinorganica (LCBI), Università degli Studi di Firenze = University of Florence [Firenze] (UNIFI), Laboratorio di Chimica Bioinorganica, Université de Namur [Namur] (UNamur), EA 4481 Groupe de Recherche Interdiscipinaire (GRIIOT), Faculté des Sciences Pharmaceutiques et Biologiques, Università degli Studi di Firenze = University of Florence [Firenze], Université de Namur [Namur], Plasticité Cellulaire et Cancer (CPAC) - U908 (CPAC), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Centre de Recherche en Cancérologie de Marseille (CRCM), Aix Marseille Université (AMU)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Catholique de Louvain (UCL), Génétique moléculaire et approches thérapeutiques des hémopathies malignes, and IRCL-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
1 (4 aminosulfonylphenyl) 3 hydroxymethyl 5 (4 bromophenyl) 1h pyrazole, Carbonate dehydratase ix inhibitor, 1 (4 aminosulfonylphenyl) 3 hydroxymethyl 5 (2 phenantryl) 1h pyrazole, Unclassified drug, Clinical Biochemistry, Cell, Pharmaceutical Science, Drug structure, Antiproliferative activity, 1 (3 aminosulfonylphenyl) 3 hydroxymethyl 5 phenyl 1h pyrazole, 01 natural sciences, Biochemistry, 1 (4 aminosulfonylphenyl) 3 hydroxymethyl 5 (4 methoxyphenyl) 1h pyrazole, 1 (4 aminosulfonylphenyl) 4 hydroxymethyl 5 (2 naphthyl) 1h pyrazole, Breast cancer, 1 (4 aminosulfonylphenyl) 3 hydroxymethyl 5 (5 bromo 6 methoxynaphtalen 2 yl) 1h pyrazole, Catalytic Domain, Drug Discovery, Cytotoxicity, Hypoxia, Carbonic Anhydrase Inhibitors, ComputingMilieux_MISCELLANEOUS, Enzyme active site, Carbonic Anhydrases, chemistry.chemical_classification, 0303 health sciences, Sulfonamides, Carbonic anhydrase, biology, Chemistry, Aryl sulfonamide inhibitors, 1 (4 aminosulfonylphenyl) 3 hydroxymethyl 5 (2 methoxyphenyl) 1h pyrazole, Carbonate dehydratase IX, 3. Good health, 1 (3 aminosulfonylphenyl) 3 hydroxymethyl 5 (6 methoxy 2 naphthalenyl) 1h pyrazole, Molecular Docking Simulation, Enzyme inhibition, medicine.anatomical_structure, Drug screening, Drug selectivity, Molecular Medicine, 1 (4 aminosulfonylphenyl) 3 hydroxymethyl 5 (6 methoxynaphtalen 2 yl) 1h pyrazole, Simulation, medicine.drug, 1 (4 aminosulfonylphenyl) 5 hydroxymethyl 3 phenyl 1h pyrazole, Protein Binding, 1 (3 aminosulfonylphenyl) 3 hydroxymethyl 5 naphthyl 1h pyrazole, Drug cytotoxicity, 1 (4 aminosulfonylphenyl) 5 hydroxymethyl 3 (2 naphthyl) 1h pyrazole, 1 (4 aminosulfonylphenyl) 3 hydroxymethyl 5 pyridinyl 1h pyrazole, Drug binding, Sulfonamide, Article, Molecular model, 03 medical and health sciences, Drug synthesis, Structure-Activity Relationship, Drug potency, [CHIM.ANAL]Chemical Sciences/Analytical chemistry, Antigens, Neoplasm, Cell Line, Tumor, medicine, Humans, Doxorubicin, 1 (4 aminosulfonylphenyl) 3 hydroxymethyl 5 (1 naphthyl) 1h pyrazole, 1 (4 aminosulfonylphenyl) 4 hydroxymethyl 5 phenyl 1h pyrazole, Carbonic Anhydrase IX, Molecular Biology, 1 (4 aminosulfonylphenyl) 3 hydroxyethyl 5 phenyl 1h pyrazole, 030304 developmental biology, Cell Proliferation, 1 (4 aminosulfonylphenyl) 4 hydroxymethyl 5 (6 methoxy 2 naphtalenyl) 1h pyrazole, Carbonate dehydratase inhibitor, Cell strain MDA MB 231, Binding Sites, 010405 organic chemistry, Organic Chemistry, Active site, In vitro, 0104 chemical sciences, 1 (4 aminosulfonylphenyl) 3 hydroxymethyl 5 (2 naphthyl) 1h pyrazole, Kinetics, Enzyme, Binding kinetics, Tumor progression, 1 (4 aminosulfonylphenyl) 3 hydroxymethyl 5 (4 tolyl) 1h pyrazole, Pyrazole, biology.protein, Pyrazoles, 1 (4 aminosulfonylphenyl) 3 hydroxymethyl 5 (3 methoxyphenyl) 1h pyrazole, 1 (4 aminosulfonylphenyl) 3 hydroxymethyl 5 phenyl 1h pyrazole, Cell line, 4 (5 aryl 2 hydroxymethyl pyrazol 1 yl)benzenesulfonamide
Abstract

Carbonic anhydrase (CA) IX expression is increased upon hypoxia and has been proposed as a therapeutic target since it has been associated with poor prognosis, tumor progression and pH regulation. We report the synthesis and the pharmacological evaluation of a new class of human carbonic anhydrase (hCA) inhibitors, 4-(5-aryl-2-hydroxymethyl-pyrazol-1-yl)-benzenesulfonamides. A molecular modeling study was conducted in order to simulate the binding mode of this new family of enzyme inhibitors within the active site of hCA IX. Pharmacological studies revealed high hCA IX inhibitory potency in the parameters nanomolar range. This study showed that the position of sulfonamide group in meta of the 1-phenylpyrazole increase a selectivity hCA IX versus hCA II of our compounds. An in vitro antiproliferative screening has been performed on the breast cancer MDA-MB-231 cell using doxorubicin as cytotoxic agent and in presence of selected CA IX inhibitor. The results shown that the cytotoxic efficiency of doxorubicin in an hypoxic environment, expressed in IC 50 value, is restored at 20% level with 1 μM CA IX inhibitor. © 2012 Elsevier Ltd. All rights reserved.

Published
2013
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13. Dasatinib in high-risk core binding factor acute myeloid leukemia in first complete remission: a French Acute Myeloid Leukemia Intergroup trial

Author

Hervé Dombret, Stephane Girault, Odile Blanchet, Romain Guieze, Céline Berthon, Christian Recher, Stéphane Leprêtre, Patrice Chevallier, Caroline Bonmati, Chantal Himberlin, Claude Preudhomme, Edouard Randriamalala, Cécile Pautas, Thomas Prebet, Eric Jourdan, Aline Renneville, Nicolas Boissel, Norbert Ifrah, Thibaut Leguay, Pascale Cornillet Lefebvre, Eric Delabesse, Thibaud Lecerf, Service d'hématologie-oncologie adultes, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Recherche clinique appliquée à l'hématologie ((EA_3518)), Université Paris Diderot - Paris 7 (UPD7), Laboratoire d'Hématologie [CHRU Lille] (Centre de Biologie et de Pathologie), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Equipe 3 - Facteurs de persistance des cellules leucémique - (INSERM U837), Institut pour la Recherche sur le Cancer de Lille (U837 INSERM - IRCL), Institut pour la recherche sur le cancer de Lille [Lille] (IRCL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre de Recherche Jean-Pierre AUBERT - Neurosciences et Cancer -JPArc [Lille]-Institut pour la recherche sur le cancer de Lille [Lille] (IRCL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre de Recherche Jean-Pierre AUBERT - Neurosciences et Cancer -JPArc [Lille], Service d’Hématologie [Hôpital Haut-Lévèque, CHU Bordeaux], CHU Bordeaux [Bordeaux]-Hôpital Haut-Lévêque [CHU de Bordeaux], Laboratoire Central d'Hématologie [Hôpital Robert Debré, CHU Reims], Centre Hospitalier Universitaire de Reims (CHU Reims)-Hôpital universitaire Robert Debré [Reims], Service d'Hématologie [CHU Toulouse], CHU Toulouse [Toulouse], Centre de Recherche en Cancérologie Nantes-Angers (CRCNA), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM)-Hôtel-Dieu de Nantes-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôpital Laennec-Centre National de la Recherche Scientifique (CNRS)-Faculté de Médecine d'Angers-Centre hospitalier universitaire de Nantes (CHU Nantes), Service des maladies du sang [CHU Angers], PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), Laboratoire d'Hématologie [Purpan], Service des Maladies du Sang [CHU Lille] (SMS), Hôpital Claude Huriez [Lille], CHU Lille-CHU Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Laboratoire d'Hématologie [CHU Angers], Service d’Hématologie [Institut Paoli Calmettes, Marseille], Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), Service d'Hématologie Biologique, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Service d'Hématologie [CHU Nantes], Centre hospitalier universitaire de Nantes (CHU Nantes), Laboratoire d'hématologie [Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), Service d'Hématologie biologique [CHU Limoges], CHU Limoges, Service d’Hématologie Adulte [Hôpitaux de Brabois, CHU Nancy], Centre Hospitalier Universitaire de Nancy (CHU Nancy), Service d’Hématologie Biologique [CHU Clermont-Ferrand], CHU Gabriel Montpied [Clermont-Ferrand], CHU Clermont-Ferrand-CHU Clermont-Ferrand-CHU Estaing [Clermont-Ferrand], CHU Clermont-Ferrand, Service d’Hématologie [Hôpital Robert Debré, CHU Reims], Service d'Hématologie [CHU Poitiers], Centre hospitalier universitaire de Poitiers (CHU Poitiers), Service d'Hématologie Clinique et Oncologie Médicale [CHU de Nîmes], Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), The authors would like to thank Bristol-Myers Squibb and the Association Laurette Fugain for their financial support., Service d’Hématologie [CHU Purpan, Toulouse], Centre Hospitalier Universitaire de Purpan (CHU Purpan), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Hôpital Purpan [Toulouse], Service des Maladies du Sang [CHRU Lille], Bernardo, Elizabeth, Institut pour la recherche sur le cancer de Lille [Lille] (IRCL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut pour la recherche sur le cancer de Lille [Lille] (IRCL)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service Hématologie - IUCT-Oncopole [CHU Toulouse], Pôle Biologie [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Pôle IUCT [CHU Toulouse], and Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)

Subjects
Adult, Male, Oncology, medicine.medical_specialty, Myeloid, Population, Dasatinib, Antineoplastic Agents, [SDV.CAN]Life Sciences [q-bio]/Cancer, Cohort Studies, Young Adult, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, [SDV.CAN] Life Sciences [q-bio]/Cancer, Maintenance therapy, Risk Factors, Internal medicine, hemic and lymphatic diseases, Humans, Medicine, education, Core binding factor acute myeloid leukemia, 030304 developmental biology, 0303 health sciences, education.field_of_study, business.industry, Core Binding Factors, Remission Induction, Myeloid leukemia, Articles, Hematology, Middle Aged, medicine.disease, 3. Good health, Leukemia, Myeloid, Acute, Leukemia, medicine.anatomical_structure, RUNX1, chemistry, 030220 oncology & carcinogenesis, Immunology, Female, France, business, Follow-Up Studies, medicine.drug
Abstract

International audience; Core-binding factor acute myeloid leukemia is a favorable acute myeloid leukemia subset cytogenetically defined by t(8;21) or inv(16)/t(16;16) rearrangements, disrupting RUNX1 (previously CBFA/AML1) or CBFB transcription factor functions. The receptor tyrosine kinase KIT is expressed in the vast majority of these acute myeloid leukemias and frequent activating KIT gene mutations have been associated with a higher risk of relapse. This phase II study aimed to evaluate dasatinib as maintenance therapy in patients with core-binding factor acute myeloid leukemia in first hematologic complete remission, but at higher risk of relapse due to molecular disease persistence or recurrence. A total of 26 patients aged 18-60 years old previously included in the CBF-2006 trial were eligible to receive dasatinib 140 mg daily if they had a poor initial molecular response (n=18) or a molecular recurrence (n=8). The tolerance of dasatinib as maintenance therapy was satisfactory. The 2-year disease-free survival in this high-risk population of patients was 25.7%. All but one patient with molecular recurrence presented subsequent hematologic relapse. Patients with slow initial molecular response had a similar disease-free survival when treated with dasatinib (40.2% at 2 years) or without any maintenance (50.0% at 2 years). The disappearance of KIT gene mutations at relapse suggests that clonal devolution may in part explain the absence of efficacy observed with single-agent dasatinib in these patients (n. EudraCT: 2006-006555-12).

Published
2015
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14. Leptin-dependent neuronal NO signaling in the preoptic hypothalamus facilitates reproduction

Author

William H. Colledge, Sebastien G. Bouret, Jyoti Parkash, Konstantina Chachlaki, Vincent Prevot, Xavier d'Anglemont de Tassigny, John Garthwaite, Nicole Bellefontaine, Charlotte Vanacker, Institut pour la Recherche sur le Cancer de Lille (U837 INSERM - IRCL), Institut pour la recherche sur le cancer de Lille [Lille] (IRCL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre de Recherche Jean-Pierre AUBERT - Neurosciences et Cancer -JPArc [Lille], Université de Lille, Droit et Santé, PRES Université Lille Nord de France, University of Cambridge [UK] (CAM), University College of London [London] (UCL), The Saban Research Institute [Los Angeles, CA, États-Unis], Children’s Hospital Los Angeles [Los Angeles]-University of Southern California (USC), Prevot, Vincent, Institut pour la recherche sur le cancer de Lille [Lille] (IRCL)-Institut National de la Santé et de la Recherche Médicale (INSERM), and University of Southern California (USC)-Children’s Hospital Los Angeles [Los Angeles]

Subjects
Leptin, Male, medicine.medical_specialty, endocrine system, Mice, 129 Strain, Nitric Oxide Synthase Type I, Biology, Nitric Oxide, Receptors, G-Protein-Coupled, 03 medical and health sciences, Mice, 0302 clinical medicine, Arcuate nucleus, Internal medicine, medicine, Animals, Humans, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Receptor, 030304 developmental biology, Mice, Knockout, Neurons, 0303 health sciences, Kisspeptins, Leptin Deficiency, Luteinizing hormone secretion, Reproduction, digestive, oral, and skin physiology, General Medicine, Luteinizing Hormone, Preoptic Area, Preoptic area, Mice, Inbred C57BL, Endocrinology, nervous system, Hypothalamus, Receptors, Leptin, Female, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Erratum, Luteinizing hormone, 030217 neurology & neurosurgery, hormones, hormone substitutes, and hormone antagonists, Receptors, Kisspeptin-1, Signal Transduction, Research Article
Abstract

International audience; The transition to puberty and adult fertility both require a minimum level of energy availability. The adipocyte-derived hormone leptin signals the long-term status of peripheral energy stores and serves as a key metabolic messenger to the neuroendocrine reproductive axis. Humans and mice lacking leptin or its receptor fail to complete puberty and are infertile. Restoration of leptin levels in these individuals promotes sexual maturation, which requires the pulsatile, coordinated delivery of gonadotropin-releasing hormone to the pituitary and the resulting surge of luteinizing hormone (LH); however, the neural circuits that control the leptin-mediated induction of the reproductive axis are not fully understood. Here, we found that leptin coordinated fertility by acting on neurons in the preoptic region of the hypothalamus and inducing the synthesis of the freely diffusible volume-based transmitter NO, through the activation of neuronal NO synthase (nNOS) in these neurons. The deletion of the gene encoding nNOS or its pharmacological inhibition in the preoptic region blunted the stimulatory action of exogenous leptin on LH secretion and prevented the restoration of fertility in leptin-deficient female mice by leptin treatment. Together, these data indicate that leptin plays a central role in regulating the hypothalamo-pituitary-gonadal axis in vivo through the activation of nNOS in neurons of the preoptic region.

Published
2014
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15. Tanycyte-like cells form a blood-cerebrospinal fluid barrier in the circumventricular organs of the mouse brain

Author

Langlet, Fanny, Mullier, Amandine, Bouret, Sebastien, Prevot, Vincent, Dehouck, Benedicte, Institut pour la Recherche sur le Cancer de Lille (U837 INSERM - IRCL), Institut pour la recherche sur le cancer de Lille [Lille] (IRCL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre de Recherche Jean-Pierre AUBERT - Neurosciences et Cancer -JPArc [Lille], NEUROBESE International Associated Laboratory [Lille], PRES Université Lille Nord de France, The Saban Research Institute [Los Angeles, CA, États-Unis], Children’s Hospital Los Angeles [Los Angeles]-University of Southern California (USC), Université d'Artois (UA), Prevot, Vincent, Institut pour la recherche sur le cancer de Lille [Lille] (IRCL)-Institut National de la Santé et de la Recherche Médicale (INSERM), and University of Southern California (USC)-Children’s Hospital Los Angeles [Los Angeles]

Subjects
Male, ependymocytes, Cell Membrane Permeability, Tight Junction Proteins, Ependymoglial Cells, Median Eminence, Brain, organum vasculosum laminae terminalis, tight junction protein, Immunohistochemistry, Antibodies, Permeability, Article, Cerebral Ventricles, Mice, Inbred C57BL, Mice, Blood-Brain Barrier, Animals, area postrema, subfornical organ, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], subcommissural organ, Cerebrospinal Fluid
Abstract

International audience; Tanycytes are highly specialized ependymal cells that form a blood-cerebrospinal fluid (CSF) barrier at the level of the median eminence (ME), a circumventricular organ (CVO) located in the tuberal region of the hypothalamus. This ependymal layer harbors well-organized tight junctions, a hallmark of central nervous system barriers that is lacking in the fenestrated portal vessels of the ME. The displacement of barrier properties from the vascular to the ventricular side allows the diffusion of blood-borne molecules into the parenchyma of the ME while tanycyte tight junctions control their diffusion into the CSF, thus maintaining brain homeostasis. In the present work, we combined immunohistochemical and permeability studies to investigate the presence of tanycyte barriers along the ventricular walls of other brain CVOs. Our data indicate that, unlike cuboidal ependymal cells, ependymal cells bordering the CVOs possess long processes that project into the parenchyma of the CVOs to reach the fenestrated capillary network. Remarkably, these tanycyte-like cells display well-organized tight junctions around their cell bodies. Consistent with these observations, permeability studies show that this ependymal layer acts as a diffusion barrier. Together, our results suggest that tanycytes are a characteristic feature of all CVOs and yield potential new insights into their involvement in regulating the exchange between the blood, the brain, and the CSF within these "brain windows."

Published
2013
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16. SEMA3A, a Gene Involved in Axonal Pathfinding, Is Mutated in Patients with Kallmann Syndrome

Author

Michel Pugeat, Charlotte Vanacker, Christine Cortet-Rudelli, Vincent Meyer, Corinne Fouveaut, Céline Campagne, Catherine Dodé, Chrystel Leroy, Stéphanie Baron, Gérard Chabrier, Jyoti Parkash, Alfons Garcia-Piñero, Vincent Prevot, Paolo Giacobini, Ksenija Gersak, Chantal Metz, Francis Collier, Cécile Espy, Jacques Young, J.-P. Hardelin, Didier Dewailly, Pierre Lhuillier, Naresh Kumar Hanchate, Corinne Cruaud, Institut pour la Recherche sur le Cancer de Lille (U837 INSERM - IRCL), Institut pour la recherche sur le cancer de Lille [Lille] (IRCL)-Institut National de la Santé et de la Recherche Médicale (INSERM), PRES Université Lille Nord de France, Ecole de Médecine [CHRU Lille], Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service de biochimie et de génétique moléculaire [CHU Cochin], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Hôpital Roger Salengro [Lille], Institut de Génomique d'Evry (IG), Université Paris-Saclay-Institut de Biologie François JACOB (JACOB), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Universitat de Barcelona (UB), Service Endocrinologie, diabétologie, maladies métaboliques et nutrition (LILLE - Endocrino), University Medical Centre Ljubljana [Ljubljana, Slovenia] (UMCL), Hôpital Morvan - CHRU de Brest (CHU - BREST ), Nouvel Hôpital Civil de Strasbourg, Hôpital neurologique et neurochirurgical Pierre Wertheimer [CHU - HCL], Hospices Civils de Lyon (HCL), AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre), Génétique des Déficits Sensoriels, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut pour la recherche sur le cancer de Lille [Lille] (IRCL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre de Recherche Jean-Pierre AUBERT - Neurosciences et Cancer -JPArc [Lille], Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut de Biologie François JACOB (JACOB), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay, Service d'Endocrinologie (LILLE - Endocrino), Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), and Prevot, Vincent

Subjects
Male, Cancer Research, Kallmann syndrome, Gonadotropin-releasing hormone, medicine.disease_cause, Gonadotropin-Releasing Hormone, Mice, Endocrinology, 0302 clinical medicine, Missense mutation, Genetics (clinical), Genetics, 0303 health sciences, Mutation, Oligogenic Inheritance, Phenotype, 3. Good health, Medicine, Female, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Research Article, Mice, 129 Strain, lcsh:QH426-470, Nose, Biology, Frameshift mutation, Molecular Genetics, 03 medical and health sciences, Fetus, medicine, Animals, Humans, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Molecular Biology, Gene, Ecology, Evolution, Behavior and Systematics, 030304 developmental biology, Semaphorin-3A, Human Genetics, Kallmann Syndrome, Neuroendocrinology, Embryo, Mammalian, medicine.disease, Axons, Neuropilin-1, Mice, Inbred C57BL, Disease Models, Animal, lcsh:Genetics, Genetics of Disease, 030217 neurology & neurosurgery
Abstract

Kallmann syndrome (KS) associates congenital hypogonadism due to gonadotropin-releasing hormone (GnRH) deficiency and anosmia. The genetics of KS involves various modes of transmission, including oligogenic inheritance. Here, we report that Nrp1 sema/sema mutant mice that lack a functional semaphorin-binding domain in neuropilin-1, an obligatory coreceptor of semaphorin-3A, have a KS–like phenotype. Pathohistological analysis of these mice indeed showed abnormal development of the peripheral olfactory system and defective embryonic migration of the neuroendocrine GnRH cells to the basal forebrain, which results in increased mortality of newborn mice and reduced fertility in adults. We thus screened 386 KS patients for the presence of mutations in SEMA3A (by Sanger sequencing of all 17 coding exons and flanking splice sites) and identified nonsynonymous mutations in 24 patients, specifically, a frameshifting small deletion (D538fsX31) and seven different missense mutations (R66W, N153S, I400V, V435I, T688A, R730Q, R733H). All the mutations were found in heterozygous state. Seven mutations resulted in impaired secretion of semaphorin-3A by transfected COS-7 cells (D538fsX31, R66W, V435I) or reduced signaling activity of the secreted protein in the GN11 cell line derived from embryonic GnRH cells (N153S, I400V, T688A, R733H), which strongly suggests that these mutations have a pathogenic effect. Notably, mutations in other KS genes had already been identified, in heterozygous state, in five of these patients. Our findings indicate that semaphorin-3A signaling insufficiency contributes to the pathogenesis of KS and further substantiate the oligogenic pattern of inheritance in this developmental disorder., Author Summary Kallmann syndrome is a hereditary developmental disease that affects both the hormonal reproductive axis and the sense of smell. There is a developmental link between the reproductive and olfactory disorders: neuroendocrine cells producing the gonadotropin-releasing hormone that is deficient in the patients normally migrate from the nose to the forebrain along olfactory nerve fibers during embryonic life, and they fail to do so in the patients. Affected individuals usually do not undergo spontaneous puberty. Hormone replacement therapy is the treatment to initiate virilization in males or breast development in females and later to develop fertility in both sexes. This is a genetically heterogeneous disease. Mutations in any of eight causative genes identified so far have been found in approximately 30% of the affected individuals, thus indicating that other genes remain to be discovered. We report on the identification, in 6% of the KS patients, of various loss-of-function mutations in the gene coding for semaphorin-3A, a secreted protein involved in the navigation of olfactory nerve fibers during embryogenesis. The fact that many of these mutations were also detected in clinically unaffected individuals indicates that they must combine with other genetic defects to produce the disease phenotype.

Published
2012
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17. Kisspeptin-GPR54 Signaling in Mouse NO-Synthesizing Neurons Participates in the Hypothalamic Control of Ovulation

Author

Xavier d'Anglemont de Tassigny, William H. Colledge, Danièle Mazur, Naresh Kumar Hanchate, Jyoti Parkash, Nicole Bellefontaine, Vincent Prevot, Prevot, Vincent, Institut pour la Recherche sur le Cancer de Lille (U837 INSERM - IRCL), Institut pour la recherche sur le cancer de Lille [Lille] (IRCL)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de médecine predictive et de recherche thérapeutique (IMPRT), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Centre Régional de Lutte contre le Cancer Oscar Lambret [Lille] (UNICANCER/Lille), Université de Lille-UNICANCER-Université de Lille-UNICANCER-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Droit et Santé-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Ecole de Médecine [CHRU Lille], Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), University of Cambridge [UK] (CAM), Institut pour la recherche sur le cancer de Lille [Lille] (IRCL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre de Recherche Jean-Pierre AUBERT - Neurosciences et Cancer -JPArc [Lille], and Université Lille Nord de France (COMUE)-UNICANCER-Université Lille Nord de France (COMUE)-UNICANCER-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Droit et Santé-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)

Subjects
Ovulation, medicine.medical_specialty, endocrine system, media_common.quotation_subject, Hypothalamus, Enzyme-Linked Immunosorbent Assay, Estrous Cycle, Nitric Oxide Synthase Type I, Biology, Inhibitory postsynaptic potential, Receptors, G-Protein-Coupled, Mice, 03 medical and health sciences, 0302 clinical medicine, Kisspeptin, Internal medicine, medicine, Animals, Premovement neuronal activity, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Enzyme Inhibitors, Phosphorylation, Receptor, PI3K/AKT/mTOR pathway, 030304 developmental biology, media_common, Mice, Knockout, Neurons, Analysis of Variance, Kisspeptins, 0303 health sciences, General Neuroscience, Articles, Luteinizing Hormone, Cell biology, Mice, Inbred C57BL, Endocrinology, Gene Expression Regulation, nervous system, Female, Steroids, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], 030217 neurology & neurosurgery, hormones, hormone substitutes, and hormone antagonists, Receptors, Kisspeptin-1, Signal Transduction
Abstract

Reproduction is controlled in the brain by a neural network that drives the secretion of gonadotropin-releasing hormone (GnRH). Various permissive homeostatic signals must be integrated to achieve ovulation in mammals. However, the neural events controlling the timely activation of GnRH neurons are not completely understood. Here we show that kisspeptin, a potent activator of GnRH neuronal activity, directly communicates with neurons that synthesize the gaseous transmitter nitric oxide (NO) in the preoptic region to coordinate the progression of the ovarian cycle. Using a transgenicGpr54-null IRES-LacZ knock-in mouse model, we demonstrate that neurons containing neuronal NO synthase (nNOS), which are morphologically associated with kisspeptin fibers, express the kisspeptin receptor GPR54 in the preoptic region, but not in the tuberal region of the hypothalamus. The activation of kisspeptin signaling in preoptic neurons promotes the activation of nNOS through its phosphorylation on serine 1412 via the AKT pathway and mimics the positive feedback effects of estrogens. Finally, we show that while NO release restrains the reproductive axis at stages of the ovarian cycle during which estrogens exert their inhibitory feedback, it is required for the kisspeptin-dependent preovulatory activation of GnRH neurons. Thus, interactions between kisspeptin and nNOS neurons may play a central role in regulating the hypothalamic–pituitary–gonadal axisin vivo.

Published
2012
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18. Analysis of Exonic Regions Involved in Nuclear Localization, Splicing Activity, and Dimerization of Muscleblind-like-1 Isoforms

Author

Edwige Van Brussels, Isabelle Behm-Ansmant, Ian Holt, Luc Buée, Nathalie Gourrier, Nicolas Sergeant, Helene Tran, Audrey Vautrin, Hélène Obriot, Claire-Marie Dhaenens, Lucie Delattre, Denis Furling, Marie-Laure Caillet-Boudin, Bernard Sablonnière, Camille Lemercier-Neuillet, Sabiha Eddarkaoui, Francisco J. Fernandez-Gomez, Christiane Branlant, Ludovic Arandel, Nicolas Charlet-Berguerand, Susanna Schraen-Maschke, Glenn E. Morris, Céline Carpentier, Institut pour la Recherche sur le Cancer de Lille (U837 INSERM - IRCL), Institut pour la recherche sur le cancer de Lille [Lille] (IRCL)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de médecine predictive et de recherche thérapeutique (IMPRT), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Centre Régional de Lutte contre le Cancer Oscar Lambret [Lille] (UNICANCER/Lille), Université de Lille-UNICANCER-Université de Lille-UNICANCER-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Droit et Santé-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), ARN-RNP, structure-fonction-maturation (AREMS), Université Henri Poincaré - Nancy 1 (UHP)-Centre National de la Recherche Scientifique (CNRS), Institut de Myologie, Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Centre de recherche en Myologie – U974 SU-INSERM, Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Robert Jones and Agnes Hunt Orthopaedic Hospital [Oswestry, UK], Keele University [Keele], Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut pour la recherche sur le cancer de Lille [Lille] (IRCL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre de Recherche Jean-Pierre AUBERT - Neurosciences et Cancer -JPArc [Lille], Université Lille Nord de France (COMUE)-UNICANCER-Université Lille Nord de France (COMUE)-UNICANCER-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Droit et Santé-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Centre National de la Recherche Scientifique (CNRS)-Université Henri Poincaré - Nancy 1 (UHP), Centre National de la Recherche Scientifique (CNRS)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Association française contre les myopathies (AFM-Téléthon)-Sorbonne Université (SU), Thérapie des maladies du muscle strié, Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Sorbonne Université (SU), and BEHM-ANSMANT, Isabelle

Subjects
Gene isoform, congenital, hereditary, and neonatal diseases and abnormalities, Exonic splicing enhancer, Active Transport, Cell Nucleus, RNA-binding protein, Biology, [SDV.BBM.BM] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Biochemistry, 03 medical and health sciences, Exon, chemistry.chemical_compound, 0302 clinical medicine, MBNL1, Humans, Myotonic Dystrophy, Protein Isoforms, Molecular Biology, 030304 developmental biology, Genetics, Cell Nucleus, 0303 health sciences, Alternative splicing, RNA-Binding Proteins, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Cell Biology, Exons, Cell biology, Alternative Splicing, chemistry, RNA splicing, RNA, Protein Multimerization, Trinucleotide Repeat Expansion, 030217 neurology & neurosurgery, Nuclear localization sequence, HeLa Cells
Abstract

International audience; Muscleblind-like-1 (MBNL1) is a splicing regulatory factor controlling the fetal-to-adult alternative splicing transitions during vertebrate muscle development. Its capture by nuclear CUG expansions is one major cause for type 1 myotonic dystro-phy (DM1). Alternative splicing produces MBNL1 isoforms that differ by the presence or absence of the exonic regions 3, 5, and 7. To understand better their respective roles and the consequences of the deregulation of their expression in DM1, here we studied the respective roles of MBNL1 alternative and constitu-tive exons. By combining genetics, molecular and cellular approaches, we found that (i) the exon 5 and 6 regions are both needed to control the nuclear localization of MBNL1; (ii) the exon 3 region strongly enhances the affinity of MBNL1 for its pre-mRNA target sites; (iii) the exon 3 and 6 regions are both required for the splicing regulatory activity, and this function is not enhanced by an exclusive nuclear localization of MBNL1; and finally (iv) the exon 7 region enhances MBNL1-MBNL1 dimerization properties. Consequently, the abnormally high inclusion of the exon 5 and 7 regions in DM1 is expected to enhance the potential of MBNL1 of being sequestered with nuclear CUG expansions, which provides new insight into DM1 pathophysiology.

Published
2011
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19. Glucose metabolism and hexosamine pathway regulate oncogene-induced senescence

Author

David Vindrieux, Delphine Gitenay, Clotilde Wiel, Hélène Simonnet, H Lallet-Daher, Sébastien Aubert, David Bernard, Léa Payen, 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], Université de Lyon, Institut de Pathologie [CHU Lille], Pôle de Biologie Pathologie Génétique [CHU Lille], Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Institut pour la Recherche sur le Cancer de Lille (U837 INSERM - IRCL), Institut pour la recherche sur le cancer de Lille [Lille] (IRCL)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hospices Civils de Lyon (HCL), We thank M Ferrand, M Samyn, M Manchon, and D Collin Chavagnac for help and materials, and other laboratory members for helpful suggestions and discussions. This work was carried out with the support of the ‘Fondation de France’, the ‘Comités de l’Ardèche et de la Drome de la Ligue nationale contre le Cancer’, the ‘Institut National du Cancer’, and the ‘RTRS Fondation Synergie Lyon Cancer’. CW is supported by the ‘Ligue contre le Cancer’ and the ‘Fondation pour la Recherche Médicale’., Hennaut, Odile, Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Institut pour la recherche sur le cancer de Lille [Lille] (IRCL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre de Recherche Jean-Pierre AUBERT - Neurosciences et Cancer -JPArc [Lille]

Subjects
Cancer Research, Time Factors, HK2, Glucose uptake, senescence-associated b-galactosidase, glucose-6-phosphate OIS, chemistry.chemical_compound, 0302 clinical medicine, Hexokinase, [CHIM] Chemical Sciences, Glycolysis, hexokinase-2, Enzyme Inhibitors, Cells, Cultured, Cellular Senescence, metabolites, 0303 health sciences, oncogene-induced senescence, 4-hydroxytamoxifen, Biochemistry, Female, Original Article, Corrigendum, Cell aging, 2-deoxy-D-glucose, PPP, glucose metabolism, adenosine triphosphate, Immunology, pentose phosphate pathway, Glucose-6-Phosphate, Carbohydrate metabolism, Pentose phosphate pathway, Biology, Transfection, 03 medical and health sciences, Cellular and Molecular Neuroscience, Humans, [CHIM]Chemical Sciences, Mammary Glands, Human, G6P, metabolites Abbreviations: 2DG, 030304 developmental biology, Epithelial Cells, Hexosamines, Oncogenes, Metabolism, Cell Biology, ATP, Kinetics, Glucose, chemistry, Glucose 6-phosphate, 4-OHT, Energy Metabolism, SA-b-Gal, 030217 neurology & neurosurgery
Abstract

A Corrigendum to this article was published on 14 August 2014 6 DOI / 10.1038/cddis.2014.360Since the publication of this paper the authors have noticed an error in the abstract section. ‘Inversely, expressing a G6P,pharmacological inhibition of HK2,’ is replaced by ‘Inversely, expressing a glucose-6-phosphatase, pharmacological inhibition of HK2,’.The corrected article appears online together with this corrigendum.The authors would like to apologize for any inconvenience caused.; International audience; Oncogenic stress-induced senescence (OIS) prevents the ability of oncogenic signals to induce tumorigenesis. It is now largely admitted that the mitogenic effect of oncogenes requires metabolic adaptations to respond to new energetic and bio constituent needs. Yet, whether glucose metabolism affects OIS response is largely unknown. This is largely because of the fact that most of the OIS cellular models are cultivated in glucose excess. In this study, we used human epithelial cells, cultivated without glucose excess, to study alteration and functional role of glucose metabolism during OIS. We report a slowdown of glucose uptake and metabolism during OIS. Increasing glucose metabolism by expressing hexokinase2 (HK2), which converts glucose to glucose-6phosphate (G6P), favors escape from OIS. Inversely, expressing a glucose-6-phosphatase, pharmacological inhibition of HK2, or adding nonmetabolizable glucose induced a premature senescence. Manipulations of various metabolites covering G6P downstream pathways (hexosamine, glycolysis, and pentose phosphate pathways) suggest an unexpected role of the hexosamine pathway in controlling OIS. Altogether, our results show that decreased glucose metabolism occurs during and participates to OIS.

Published
2014
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