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An Autocrine Activinb Mechanism Drives TGF /Activin Signaling In An autocrine ActivinB mechanism drives TGF β/Activin signaling in Group 3 medulloblastoma Morgane Morabito, Magalie Larcher, Florence M G Cavalli, Chloé Foray, Antoine Forget, Liliana Mirabal-ortega, Mamy Andrianteranagna, Sabine Druillennec, Alexandra Garancher, Julien Masliah-planchon, et al. To cite this version: Morgane Morabito, Magalie Larcher, Florence M G Cavalli, Chloé Foray, Antoine Forget, et al.. An autocrine ActivinB mechanism drives TGF β/Activin signaling in Group 3 medulloblastoma. EMBO Molecular Medicine, Wiley Open Access, 2019, 6, pp.e9830. 10.15252/emmm.201809830. hal-02347105 HAL Id: hal-02347105 https://hal.archives-ouvertes.fr/hal-02347105 Submitted on 5 Nov 2019 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. Article An autocrine ActivinB mechanism drives TGFb/ Activin signaling in Group 3 medulloblastoma Morgane Morabito1,2,3,4,5, Magalie Larcher1,2,3,4,5, Florence MG Cavalli6,7, Chloé Foray1,2,3,4,5, Antoine Forget1,2,3,4,5, Liliana Mirabal-Ortega1,2,3,4,5, Mamy Andrianteranagna5,8,9,10,11,12,13, Sabine Druillennec1,2,3,4,5, Alexandra Garancher1,2,3,4,5, Julien Masliah-Planchon5,8,9,11, Sophie Leboucher1,4, Abel Debalkew6,7, Alessandro Raso14, Olivier Delattre5,8,9,11, Stéphanie Puget15,16, François Doz8,11,15, Michael D Taylor6,7,17,18, Olivier Ayrault1,2,3,4,5, Franck Bourdeaut5,8,9,10,11, Alain Eychène1,2,3,4,5 & Celio Pouponnot1,2,3,4,5,* Abstract Keywords activin; medulloblastoma; Smad2; Smad3; TGFbeta Subject Category Cancer Medulloblastoma (MB) is a pediatric tumor of the cerebellum DOI 10.15252/emmm.201809830 | Received 19 September 2018 | Revised 28 divided into four groups. Group 3 is of bad prognosis and June 2019 | Accepted 2 July 2019 remains poorly characterized. While the current treatment EMBO Mol Med (2019)e9830 involving surgery, radiotherapy, and chemotherapy often fails, no alternative therapy is yet available. Few recurrent genomic alterations that can be therapeutically targeted have been iden- Introduction tified. Amplifications of receptors of the TGFb/Activin pathway occur at very low frequency in Group 3 MB. However, neither Medulloblastoma (MB), a cerebellar tumor, is one of the most their functional relevance nor activation of the downstream common malignant brain tumors in children (Holgado et al, 2017; signaling pathway has been studied. We showed that this path- Wang et al, 2018). Current therapy associates surgery, chemother- way is activated in Group 3 MB with some samples showing a apy, and radiotherapy. This aggressive regimen allowed an increase very strong activation. Beside genetic alterations, we demon- in the overall survival rate up to 70–80% but induces dramatic long- strated that an ActivinB autocrine stimulation is responsible for term side effects (Martin et al, 2014). In addition, the overall pathway activation in a subset of Group 3 MB characterized by survival rate of high-risk patients is far below (Holgado et al, 2017; high PMEPA1 levels. Importantly, Galunisertib, a kinase inhibitor Wang et al, 2018). It is therefore crucial to identify new treatments of the cognate receptors currently tested in clinical trials for that decrease side effects and improve efficacy. Glioblastoma patients, showed efficacy on orthotopically grafted Genomic and transcriptomic approaches allowed the stratifi- MB-PDX. Our data demonstrate that the TGFb/Activin pathway is cation of MB patients into 4 different molecular groups: WNT (Win- active in a subset of Group 3 MB and can be therapeutically gless), SHH (Sonic Hedgehog), Group 3, and Group 4 (Northcott targeted. et al, 2012a; Taylor et al, 2012). These groups display differences in 1 Institut Curie, Orsay, France 2 INSERM U1021, Centre Universitaire, Orsay, France 3 CNRS UMR 3347, Centre Universitaire, Orsay, France 4 University Paris Sud – Paris-Saclay, Orsay, France 5 PSL Research University, Paris, France 6 The Arthur and Sonia Labatt Brain Tumour Research Center, The Hospital for Sick Children, Toronto, ON, Canada 7 Developmental and Stem Cell Biology Program, The Hospital for Sick Children, Toronto, ON, Canada 8 Institut Curie, Paris, France 9 INSERM U830, Paris, France 10 Translational Research in Pediatric Oncology, Institut Curie SiRIC, Paris, France 11 SIREDO Center (Care, innovation, Research in pediatric, adolescent and young adult oncology), Institut Curie, Paris, France 12 INSERM, U900, Paris, France 13 MINES ParisTech, CBIO-Centre for Computational Biology, Paris, France 14 Department of Patology, ASL 3 Genovese, SC Laboratorio d’Analisi, Genova, Italy 15 Université Paris Descartes, Sorbonne Paris Cité, Paris, France 16 Département Neurochirurgie Pédiatrique, AP-HP, Hôpital Necker-Enfants Malades, Paris, France 17 Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada 18 Division of Neurosurgery, The Hospital for Sick Children, Toronto, ON, Canada *Corresponding author. Tel: +33 1 69 86 30 79; Fax: +33 1 69 86 30 51; E-mail: [email protected] ª 2019 The Authors. Published under the terms of the CC BY 4.0 license EMBO Molecular Medicine e9830 | 2019 1 of 17 EMBO Molecular Medicine Morgane Morabito et al terms of cell of origin, transcriptional, epigenetic, and mutational TGFb signaling, which has been suggested to be deregulated in few signatures. They also differ in their clinical characteristics such as Group 3 MB, although no functional data have been reported so far. histology, overall survival rate, and presence of metastases. A study on structural genomic variations across over 1,000 MB has Recently, intragroup heterogeneity has been further uncovered, first described few amplifications of different mediators of the allowing their division into subtypes with some specific clinical TGFb/Activin pathway in Group 3 MB (Northcott et al, 2012b). parameters as well as genomic alterations (Cavalli et al, 2017a; They include ACVR2A and ACVR2B, two type II receptors for Northcott et al, 2017; Schwalbe et al, 2017). Although the existence Activin, as well as TGFBR1, a type I receptor for TGFb, highlighting of subdivisions within the different groups is clear, the outlines of a potential deregulation of Smad2/3 signaling (see below). Addition- the different subtypes have not completely reached a consensus so ally, since OTX2 has been demonstrated to be a target gene of this far. The WNT group represents 10% of all MBs and is driven by signaling pathway (Jia et al, 2009), it has been proposed that OTX2 constitutive activation of the WNT/b-catenin pathway with patients amplifications could represent a mechanism by which the pathway showing the best prognosis. The SHH group accounts for 20–25% of is also deregulated downstream (Northcott et al, 2012b). The puta- MB and is characterized by mutations involving different mediators tive significance of this signaling pathway in Group 3 was reinforced of the SHH pathway. It is considered of intermediate prognosis. by two subsequent studies, one involving sequencing in a large However, recent sub-classifications identified SHH subtypes with cohort of MB (Northcott et al, 2017) and the other showing that poorer outcomes (Cavalli et al, 2017a; Schwalbe et al, 2017). On the several components of this signaling pathway could also be deregu- other side, Group 3 and Group 4 are far less characterized due to lated at their expression level, through Group 3-specific enhancers their genetic and clinical heterogeneity. They display some degrees (Lin et al, 2016). Although these studies might indicate a potential of overlap with a few samples (~10%) being difficult to specifically deregulation of the Smad2/3 signaling pathway, this could account assign to either Group. They share some clinical characteristics, for only a modest proportion of Group 3 tumors. such as a high propensity to metastasis and genetic alterations such The TGFb superfamily is a large family of cytokines divided into as OTX2 amplifications or KBTBD4 mutations (Northcott et al, two distinct groups of ligands: the TGFbs/Activins and the BMPs. 2017). In contrast to SHH and WNT groups, no deregulation of a TGFb/Activin ligands signal through Smad2/3. These ligands bring given signaling pathway has been yet reported. Group 4 represents together two types of serine/threonine kinase receptors, the type I 35–40% of all MB patients and shows, in few cases, MYCN and and the type II, which are specific for a set of ligands. The TGFbs CDK6 amplifications and KDM6A mutations. Recently, it has been (TGFb1, TGFb2, and TGFb3) signal through the TGFBR1 type I and shown that genomic alterations involving enhancer hijacking induce TGFBR2 type II receptors. Activin, encoded by 4 different genes, PRDM6 overexpression in 15–20% of Group 4 (Northcott et al, INHBA, INHBB, INHBC, and INHBE, can activate different couples of 2017). Group 3 represents 20–25% of MB patients and is associated receptors including the ACVR2A and ACVR2B type II and ACVR1A with bad prognosis. This group is highly metastatic and character- (ALK4) and ACVR1C (ALK7) type I receptors. INHA, encoding ized by MYC overexpression,
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