1. An autocrine ActivinB mechanism drives TGFβ/Activin signaling in Group 3 medulloblastoma
- Author
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Alessandro Raso, Alain Eychène, Antoine Forget, Michael D. Taylor, Morgane Morabito, Magalie Larcher, Franck Bourdeaut, Florence M.G. Cavalli, Liliana Mirabal-Ortega, Olivier Delattre, Chloe Foray, Abel Debalkew, François Doz, Julien Masliah-Planchon, Sophie Leboucher, Celio Pouponnot, Alexandra Garancher, Mamy Andrianteranagna, Stéphanie Puget, Sabine Druillennec, Olivier Ayrault, Department of Anatomy and Cell Biology [Montréal], McGill University, Signalisation normale et pathologique de l'embryon aux thérapies innovante des cancers, Institut Curie-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Unité de génétique et biologie des cancers (U830), Université Paris Descartes - Paris 5 (UPD5)-Institut Curie-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Bioinformatique (CBIO), MINES ParisTech - École nationale supérieure des mines de Paris-PSL Research University (PSL), Cancer et génôme: Bioinformatique, biostatistiques et épidémiologie d'un système complexe, MINES ParisTech - École nationale supérieure des mines de Paris-Institut Curie-Institut National de la Santé et de la Recherche Médicale (INSERM), PSL Research University (PSL), Institut Curie, Université Paris Sud Orsay, Université Paris Descartes - Paris 5 (UPD5), CHU Necker - Enfants Malades [AP-HP], Signalisation cellulaire et neurobiologie (SNC), McGill University = Université McGill [Montréal, Canada], Signalisation normale et pathologique de l'embryon aux thérapies innovantes des cancers, Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5), MINES ParisTech - École nationale supérieure des mines de Paris, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL), Cancer et génome: Bioinformatique, biostatistiques et épidémiologie d'un système complexe, Institut Curie [Paris]-MINES ParisTech - École nationale supérieure des mines de Paris, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris sciences et lettres (PSL), Institut Curie [Paris], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)
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0301 basic medicine ,Cerebellum ,Medicine (General) ,medicine.medical_treatment ,[SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology ,Apoptosis ,Smad2 Protein ,QH426-470 ,0302 clinical medicine ,Transforming Growth Factor beta ,Phosphorylation ,Receptor ,Cancer ,Inhibin-beta Subunits ,activin ,Articles ,3. Good health ,Tumor Burden ,Gene Expression Regulation, Neoplastic ,Autocrine Communication ,medicine.anatomical_structure ,TGFbeta ,Quinolines ,Molecular Medicine ,Female ,Signal Transduction ,Mice, Nude ,[SDV.CAN]Life Sciences [q-bio]/Cancer ,Antineoplastic Agents ,medulloblastoma ,Article ,TGFbeta Subject Category Cancer ,Transforming Growth Factor beta1 ,03 medical and health sciences ,R5-920 ,Transforming Growth Factor beta3 ,[SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN] ,Cell Line, Tumor ,medicine ,Genetics ,Galunisertib ,Animals ,Humans ,Smad3 Protein ,Autocrine signalling ,Cerebellar Neoplasms ,Cell Proliferation ,Medulloblastoma ,Chemotherapy ,business.industry ,Mechanism (biology) ,Membrane Proteins ,medicine.disease ,Xenograft Model Antitumor Assays ,Radiation therapy ,030104 developmental biology ,Cancer research ,Pyrazoles ,business ,030217 neurology & neurosurgery ,Smad2 ,Smad3 - Abstract
International audience; Medulloblastoma (MB) is a pediatric tumor of the cerebellum divided into four groups. Group 3 is of bad prognosis and remains poorly characterized. While the current treatment involving surgery, radiotherapy, and chemotherapy often fails, no alternative therapy is yet available. Few recurrent genomic alterations that can be therapeutically targeted have been identified. Amplifications of receptors of the TGFb/Activin pathway occur at very low frequency in Group 3 MB. However, neither their functional relevance nor activation of the downstream signaling pathway has been studied. We showed that this pathway is activated in Group 3 MB with some samples showing a very strong activation. Beside genetic alterations, we demonstrated that an ActivinB autocrine stimulation is responsible for pathway activation in a subset of Group 3 MB characterized by high PMEPA1 levels. Importantly, Galunisertib, a kinase inhibitor of the cognate receptors currently tested in clinical trials for Glioblastoma patients, showed efficacy on orthotopically grafted MB-PDX. Our data demonstrate that the TGFb/Activin pathway is active in a subset of Group 3 MB and can be therapeutically targeted.
- Published
- 2019
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