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5 results on '"Jonathan Blachier"'

1. Targeting netrin‐1/DCC interaction in diffuse large B‐cell and mantle cell lymphomas

Author

Laura Broutier, Marion Creveaux, Jonathan Vial, Antonin Tortereau, Jean‐Guy Delcros, Guillaume Chazot, Mark J McCarron, Sophie Léon, Céline Pangault, Nicolas Gadot, Amélie Colombe, Marie‐Laure Boulland, Jonathan Blachier, Julien C Marie, Alexandra Traverse‐Glehen, Olivier Donzé, Catherine Chassagne‐Clément, Gilles Salles, Karin Tarte, Patrick Mehlen, and Marie Castets

Subjects
apoptosis, dependence receptors, non‐Hodgkin lymphoma, DCC, netrin‐1, Medicine (General), R5-920, Genetics, QH426-470
Abstract

Abstract DCC (Deleted in Colorectal Carcinoma) has been demonstrated to constrain tumor progression by inducing apoptosis unless engaged by its ligand netrin‐1. This has been shown in breast and colorectal cancers; however, this tumor suppressive function in other cancers is not established. Using a transgenic mouse model, we report here that inhibition of DCC‐induced apoptosis is associated with lymphomagenesis. In human diffuse large B‐cell lymphoma (DLBCL), an imbalance of the netrin‐1/DCC ratio suggests a loss of DCC‐induced apoptosis, either via a decrease in DCC expression in germinal center subtype or by up‐regulation of netrin‐1 in activated B‐cell (ABC) one. Such imbalance is also observed in mantle cell lymphoma (MCL). Using a netrin‐1 interfering antibody, we demonstrate both in vitro and in vivo that netrin‐1 acts as a survival factor for ABC‐DLBCL and MCL tumor cells. Together, these data suggest that interference with the netrin‐1/DCC interaction could represent a promising therapeutic strategy in netrin‐1‐positive DLBCL and MCL.

Published
2016
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2. Hey1- and p53-dependent TrkC proapoptotic activity controls neuroblastoma growth.

Author

Marie Ménard, Clélia Costechareyre, Gabriel Ichim, Jonathan Blachier, David Neves, Loraine Jarrosson-Wuilleme, Reinhard Depping, Jan Koster, Pierre Saintigny, Patrick Mehlen, and Servane Tauszig-Delamasure

Subjects
Biology (General), QH301-705.5
Abstract

The neurotrophin-3 (NT-3) receptor tropomyosin receptor kinase C (TrkC/NTRK3) has been described as a dependence receptor and, as such, triggers apoptosis in the absence of its ligand NT-3. This proapoptotic activity has been proposed to confer a tumor suppressor activity to this classic tyrosine kinase receptor (RTK). By investigating interacting partners that might facilitate TrkC-induced cell death, we have identified the basic helix-loop-helix (bHLH) transcription factor Hey1 and importin-α3 (karyopherin alpha 4 [KPNA4]) as direct interactors of TrkC intracellular domain, and we show that Hey1 is required for TrkC-induced apoptosis. We propose here that the cleaved proapoptotic portion of TrkC intracellular domain (called TrkC killer-fragment [TrkC-KF]) is translocated to the nucleus by importins and interacts there with Hey1. We also demonstrate that Hey1 and TrkC-KF transcriptionally silence mouse double minute 2 homolog (MDM2), thus contributing to p53 stabilization. p53 transcriptionally regulates the expression of TrkC-KF cytoplasmic and mitochondrial interactors cofactor of breast cancer 1 (COBRA1) and B cell lymphoma 2-associated X (BAX), which will subsequently trigger the intrinsic pathway of apoptosis. Of interest, TrkC was proposed to constrain tumor progression in neuroblastoma (NB), and we demonstrate in an avian model that TrkC tumor suppressor activity requires Hey1 and p53.

Published
2018
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4. Targeting netrin‐1/ <scp>DCC</scp> interaction in diffuse large B‐cell and mantle cell lymphomas

Author

Catherine Chassagne-Clément, Jean-Guy Delcros, Marie Castets, Jonathan Vial, Antonin Tortereau, Amélie Colombe, Gilles Salles, Céline Pangault, Sophie Léon, Karin Tarte, Guillaume Chazot, Olivier Donzé, Nicolas Gadot, Patrick Mehlen, Laura Broutier, Marion Creveaux, Mark J. McCarron, Jonathan Blachier, Julien C. Marie, Alexandra Traverse-Glehen, Marie-Laure Boulland, 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), Développement Cancer et Thérapies Ciblées [Lyon] (LabEx DEVweCAN), Université de Lyon, Interactions Cellules Environnement - UR (ICE), VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS), Microenvironnement et cancer (MiCa), Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Anipath, UFR Médecine Lyon-RTH Laennec, Service d'Hématologie, Immunologie et de Thérapie Cellulaire (HITC), Université de Rennes (UR)-Hôpital Pontchaillou-CHU Pontchaillou [Rennes], Laboratoire de Biologie Moléculaire de la Cellule (LBMC), École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Service d'Anatomie Pathologique, Hospices Civils de Lyon (HCL), Département d'anatomopathologie, biopathologie, Centre Léon Bérard [Lyon], Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Service d’immunologie, de thérapie cellulaire et d’hématopoïèse, Hôpital Pontchaillou, Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Hôpital Pontchaillou-CHU Pontchaillou [Rennes], Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), and Université de Lyon-Université de Lyon

Subjects
0301 basic medicine, Pathology, Deleted in Colorectal Cancer, [SDV]Life Sciences [q-bio], Cell, Lymphoma, Mantle-Cell, Mice, immune system diseases, hemic and lymphatic diseases, Netrin, non‐Hodgkin lymphoma, DCC, Cancer, non-Hodgkin lymphoma, apoptosis, Netrin-1, DCC Receptor, 3. Good health, netrin‐1, medicine.anatomical_structure, embryonic structures, Heterografts, Molecular Medicine, Lymphoma, Large B-Cell, Diffuse, Protein Binding, medicine.medical_specialty, animal structures, Antineoplastic Agents, Mice, Transgenic, Receptors, Cell Surface, Biology, Antibodies, 03 medical and health sciences, Cell Line, Tumor, Report, dependence receptors, medicine, Animals, Humans, Nerve Growth Factors, B cell, Tumor Suppressor Proteins, fungi, Germinal center, medicine.disease, Lymphoma, Disease Models, Animal, 030104 developmental biology, Tumor progression, Cancer research, Mantle cell lymphoma, Haematology, Reports
Abstract

International audience; DCC (Deleted in Colorectal Carcinoma) has been demonstrated to constrain tumor progression by inducing apoptosis unless engaged by its ligand netrin-1. This has been shown in breast and colorectal cancers; however, this tumor suppressive function in other cancers is not established. Using a transgenic mouse model, we report here that inhibition of DCC-induced apoptosis is associated with lymphomagenesis. In human diffuse large B-cell lymphoma (DLBCL), an imbalance of the netrin-1/DCC ratio suggests a loss of DCC-induced apoptosis, either via a decrease in DCC expression in germinal center subtype or by up-regulation of netrin-1 in activated B-cell (ABC) one. Such imbalance is also observed in mantle cell lymphoma (MCL). Using a netrin-1 interfering antibody, we demonstrate both in vitro and in vivo that netrin-1 acts as a survival factor for ABC-DLBCL and MCL tumor cells. Together, these data suggest that interference with the netrin-1/DCC interaction could represent a promising therapeutic strategy in netrin-1-positive DLBCL and MCL

Published
2016

5. The dependence receptor TrkC regulates the number of sensory neurons during DRG development

Author

Loraine Jarrosson-Wuilleme, Muriel Bozon, Elisabeth Dupin, Karine Kindbeiter, Clélia Costechareyre, Marie Ménard, Juliana M. Coelho-Aguiar, Patrick Mehlen, Jorge Ruben Cabrera, Jonathan Blachier, Nicole M. Le Douarin, Nicolas Rama, Servane Tauszig-Delamasure, Apoptosis, Cancer and Development Laboratory [Lyon], Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Instituto Estadual do cerebro Paulo Niemeyer, Centre de génétique et de physiologie moléculaire et cellulaire (CGPhiMC), Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon, Institut de la Vision, Centre National de la Recherche Scientifique (CNRS)-Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Développement Cancer et Thérapies Ciblées [Lyon] (LabEx DEVweCAN), Université de Lyon, Apoptose Cancer et Développement, Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), and Tauszig-Delamasure, Servane

Subjects
0301 basic medicine, Male, Programmed cell death, animal structures, Sensory Receptor Cells, Cell Survival, [SDV]Life Sciences [q-bio], Apoptosis, Mice, Transgenic, Dependence receptor, Chick Embryo, Biology, Tropomyosin receptor kinase C, Cell Line, 03 medical and health sciences, Mice, 0302 clinical medicine, Ganglia, Spinal, medicine, Gene silencing, Animals, Receptor, trkC, Nerve Growth Factors, Molecular Biology, ComputingMilieux_MISCELLANEOUS, Neurogenesis, Neural tube, Cell Biology, Cell biology, [SDV] Life Sciences [q-bio], Mice, Inbred C57BL, 030104 developmental biology, medicine.anatomical_structure, nervous system, biology.protein, Female, Neuron, 030217 neurology & neurosurgery, Developmental Biology, Neurotrophin
Abstract

The development of the sensory nervous system is the result of fine-tuned waves of neurogenesis and apoptosis which control the appropriate number of precursors and newly generated neurons and orient them toward a specific lineage. Neurotrophins and their tyrosine-kinase receptors (RTK) orchestrate this process. They have long been in the scope of the neurotrophic theory which established that a neuron is committed to die unless a trophic factor generated by its target provides it with a survival signal. The neural death has thus always been described as a "default" program, survival being the major player to control the number of cells. New insights have been brought by the gain of function studies which recently demonstrated that TrkC (NTRK3) is a "dependence receptor" able to actively trigger apoptosis in absence of its ligand NT-3. In order to address the role of TrkC pro-apoptotic activity in the control of sensory neurons number, we generated a TrkC gene-trap mutant mice. We found out that this new murine model recapitulates the sensory phenotype of TrkC constitutive mutants, with reduced DRG size and reduced number of DRG neurons. We engineered these mice strain with a lacZ reporter in order to follow the fate of neurons committed to a TrkC lineage and observed that they are specifically protected from NT-3 mediated apoptosis in NT-3/TrkC double knock-out embryos. Finally, using a chicken model we demonstrated that silencing NT-3 emanating from the ventral neural tube induced apoptosis in the DRG anlage. This apoptosis was inhibited by silencing TrkC. This work thus demonstrates that, during in vivo DRG development, TrkC behaves as a two-sided receptor transducing positive signals of neuronal survival in response to NT-3, but actively inducing neuronal cell death when unbound. This functional duality sets adequate number of neurons committed to a TrkC identity in the forming DRG.

Published
2018

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