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      • Record: found
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      An autocrine ActivinB mechanism drives TGFβ/Activin signaling in Group 3 medulloblastoma

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      EMBO Molecular Medicine

      John Wiley and Sons Inc.

      activin, medulloblastoma, Smad2, Smad3, TGFbeta, Cancer

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          Abstract

          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 TGFβ/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 MBPDX. Our data demonstrate that the TGFβ/Activin pathway is active in a subset of Group 3 MB and can be therapeutically targeted.

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          Most cited references 55

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          TGFbeta in Cancer.

          The transforming growth factor beta (TGFbeta) signaling pathway is a key player in metazoan biology, and its misregulation can result in tumor development. The regulatory cytokine TGFbeta exerts tumor-suppressive effects that cancer cells must elude for malignant evolution. Yet, paradoxically, TGFbeta also modulates processes such as cell invasion, immune regulation, and microenvironment modification that cancer cells may exploit to their advantage. Consequently, the output of a TGFbeta response is highly contextual throughout development, across different tissues, and also in cancer. The mechanistic basis and clinical relevance of TGFbeta's role in cancer is becoming increasingly clear, paving the way for a better understanding of the complexity and therapeutic potential of this pathway.
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            Molecular subgroups of medulloblastoma: the current consensus

            Medulloblastoma, a small blue cell malignancy of the cerebellum, is a major cause of morbidity and mortality in pediatric oncology. Current mechanisms for clinical prognostication and stratification include clinical factors (age, presence of metastases, and extent of resection) as well as histological subgrouping (classic, desmoplastic, and large cell/anaplastic histology). Transcriptional profiling studies of medulloblastoma cohorts from several research groups around the globe have suggested the existence of multiple distinct molecular subgroups that differ in their demographics, transcriptomes, somatic genetic events, and clinical outcomes. Variations in the number, composition, and nature of the subgroups between studies brought about a consensus conference in Boston in the fall of 2010. Discussants at the conference came to a consensus that the evidence supported the existence of four main subgroups of medulloblastoma (Wnt, Shh, Group 3, and Group 4). Participants outlined the demographic, transcriptional, genetic, and clinical differences between the four subgroups. While it is anticipated that the molecular classification of medulloblastoma will continue to evolve and diversify in the future as larger cohorts are studied at greater depth, herein we outline the current consensus nomenclature, and the differences between the medulloblastoma subgroups.
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              Subgroup-specific structural variation across 1,000 medulloblastoma genomes.

              Medulloblastoma, the most common malignant paediatric brain tumour, is currently treated with nonspecific cytotoxic therapies including surgery, whole-brain radiation, and aggressive chemotherapy. As medulloblastoma exhibits marked intertumoural heterogeneity, with at least four distinct molecular variants, previous attempts to identify targets for therapy have been underpowered because of small samples sizes. Here we report somatic copy number aberrations (SCNAs) in 1,087 unique medulloblastomas. SCNAs are common in medulloblastoma, and are predominantly subgroup-enriched. The most common region of focal copy number gain is a tandem duplication of SNCAIP, a gene associated with Parkinson's disease, which is exquisitely restricted to Group 4α. Recurrent translocations of PVT1, including PVT1-MYC and PVT1-NDRG1, that arise through chromothripsis are restricted to Group 3. Numerous targetable SCNAs, including recurrent events targeting TGF-β signalling in Group 3, and NF-κB signalling in Group 4, suggest future avenues for rational, targeted therapy.
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                Author and article information

                Contributors
                celio.pouponnot@curie.fr
                Journal
                EMBO Mol Med
                EMBO Mol Med
                10.1002/(ISSN)1757-4684
                EMMM
                embomm
                EMBO Molecular Medicine
                John Wiley and Sons Inc. (Hoboken )
                1757-4676
                1757-4684
                22 July 2019
                August 2019
                : 11
                : 8 ( doiID: 10.1002/emmm.v11.8 )
                Affiliations
                [ 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
                Author notes
                [* ]Corresponding author. Tel: +33 1 69 86 30 79; Fax: +33 1 69 86 30 51; E‐mail: celio.pouponnot@ 123456curie.fr
                Article
                EMMM201809830
                10.15252/emmm.201809830
                6685082
                31328883
                © 2019 The Authors. Published under the terms of the CC BY 4.0 license

                This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

                Counts
                Figures: 11, Tables: 0, Pages: 17, Words: 13817
                Product
                Funding
                Funded by: Ligue Contre le Cancer
                Award ID: M18759
                Award ID: M16649
                Award ID: Leg Chovet
                Funded by: Ministère Français de l'Enseignement Supérieur (MSRE)
                Funded by: Fondation ARC pour la Recherche sur le Cancer (ARC)
                Funded by: Institut National Du Cancer (INCa)
                Categories
                Article
                Articles
                Custom metadata
                2.0
                emmm201809830
                August 2019
                Converter:WILEY_ML3GV2_TO_NLMPMC version:5.6.7 mode:remove_FC converted:07.08.2019

                Molecular medicine

                tgfbeta, smad3, smad2, medulloblastoma, activin, cancer

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