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      An autocrine ActivinB mechanism drives TGFβ/Activin signaling in Group 3 medulloblastoma

      research-article
      Author(s): 1 , 2 , 3 , 4 , 5 , 1 , 2 , 3 , 4 , 5 , 6 , 7 , 1 , 2 , 3 , 4 , 5 , 1 , 2 , 3 , 4 , 5 , 1 , 2 , 3 , 4 , 5 , 5 , 8 , 9 , 10 , 11 , 12 , 13 , 1 , 2 , 3 , 4 , 5 , 1 , 2 , 3 , 4 , 5 , 5 , 8 , 9 , 11 , 1 , 4 , 6 , 7 , 14 , 5 , 8 , 9 , 11 , 15 , 16 , 8 , 11 , 15 , 6 , 7 , 17 , 18 , 1 , 2 , 3 , 4 , 5 , 5 , 8 , 9 , 10 , 11 , 1 , 2 , 3 , 4 , 5 , 1 , 2 , 3 , 4 , 5 ,
      Publication date (Electronic):
      Journal: EMBO Molecular Medicine
      Publisher: John Wiley and Sons Inc.
      Keywords: 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 MB‐ PDX. 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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          Tgf-beta superfamily signaling in embryonic development and homeostasis.

          Mary Y. Wu, Caroline Hill (2009)
          TGF-beta superfamily signaling pathways emerged with the evolution of multicellular animals, suggesting that these pathways contribute to the increased diversity and complexity required for the development and homeostasis of these organisms. In this review we begin by exploring some key developmental and disease processes requiring TGF-beta ligands to underscore the fundamental importance of these pathways before delving into the molecular mechanism of signal transduction, focusing on recent findings. Finally, we discuss how these ligands act as morphogens, how their activity and signaling range is regulated, and how they interact with other signaling pathways to achieve their specific and varied functional roles.
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            Integrative genomic analysis of medulloblastoma identifies a molecular subgroup that drives poor clinical outcome.

            Yoon-Jae Cho, Aviad Tsherniak, Pablo Tamayo … (2011)
            Medulloblastomas are heterogeneous tumors that collectively represent the most common malignant brain tumor in children. To understand the molecular characteristics underlying their heterogeneity and to identify whether such characteristics represent risk factors for patients with this disease, we performed an integrated genomic analysis of a large series of primary tumors. We profiled the mRNA transcriptome of 194 medulloblastomas and performed high-density single nucleotide polymorphism array and miRNA analysis on 115 and 98 of these, respectively. Non-negative matrix factorization-based clustering of mRNA expression data was used to identify molecular subgroups of medulloblastoma; DNA copy number, miRNA profiles, and clinical outcomes were analyzed for each. We additionally validated our findings in three previously published independent medulloblastoma data sets. Identified are six molecular subgroups of medulloblastoma, each with a unique combination of numerical and structural chromosomal aberrations that globally influence mRNA and miRNA expression. We reveal the relative contribution of each subgroup to clinical outcome as a whole and show that a previously unidentified molecular subgroup, characterized genetically by c-MYC copy number gains and transcriptionally by enrichment of photoreceptor pathways and increased miR-183∼96∼182 expression, is associated with significantly lower rates of event-free and overall survivals. Our results detail the complex genomic heterogeneity of medulloblastomas and identify a previously unrecognized molecular subgroup with poor clinical outcome for which more effective therapeutic strategies should be developed.
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              Integrated Genomics Identifies Five Medulloblastoma Subtypes with Distinct Genetic Profiles, Pathway Signatures and Clinicopathological Features

              Marcel Kool, Jan Koster, Jens Bunt … (2008)
              Background Medulloblastoma is the most common malignant brain tumor in children. Despite recent improvements in cure rates, prediction of disease outcome remains a major challenge and survivors suffer from serious therapy-related side-effects. Recent data showed that patients with WNT-activated tumors have a favorable prognosis, suggesting that these patients could be treated less intensively, thereby reducing the side-effects. This illustrates the potential benefits of a robust classification of medulloblastoma patients and a detailed knowledge of associated biological mechanisms. Methods and Findings To get a better insight into the molecular biology of medulloblastoma we established mRNA expression profiles of 62 medulloblastomas and analyzed 52 of them also by comparative genomic hybridization (CGH) arrays. Five molecular subtypes were identified, characterized by WNT signaling (A; 9 cases), SHH signaling (B; 15 cases), expression of neuronal differentiation genes (C and D; 16 and 11 cases, respectively) or photoreceptor genes (D and E; both 11 cases). Mutations in β-catenin were identified in all 9 type A tumors, but not in any other tumor. PTCH1 mutations were exclusively identified in type B tumors. CGH analysis identified several fully or partly subtype-specific chromosomal aberrations. Monosomy of chromosome 6 occurred only in type A tumors, loss of 9q mostly occurred in type B tumors, whereas chromosome 17 aberrations, most common in medulloblastoma, were strongly associated with type C or D tumors. Loss of the inactivated X-chromosome was highly specific for female cases of type C, D and E tumors. Gene expression levels faithfully reflected the chromosomal copy number changes. Clinicopathological features significantly different between the 5 subtypes included metastatic disease and age at diagnosis and histology. Metastatic disease at diagnosis was significantly associated with subtypes C and D and most strongly with subtype E. Patients below 3 yrs of age had type B, D, or E tumors. Type B included most desmoplastic cases. We validated and confirmed the molecular subtypes and their associated clinicopathological features with expression data from a second independent series of 46 medulloblastomas. Conclusions The new medulloblastoma classification presented in this study will greatly enhance the understanding of this heterogeneous disease. It will enable a better selection and evaluation of patients in clinical trials, and it will support the development of new molecular targeted therapies. Ultimately, our results may lead to more individualized therapies with improved cure rates and a better quality of life.
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                Author and article information

                Contributors
                Celio Pouponnot:
                ORCID: https://orcid.org/0000-0002-9795-0496
                celio.pouponnot@curie.fr
                Journal
                Journal ID (nlm-ta): EMBO Mol Med
                Journal ID (iso-abbrev): EMBO Mol Med
                Journal ID (doi): 10.1002/(ISSN)1757-4684
                Journal ID (publisher-id): EMMM
                Journal ID (hwp): embomm
                Title: EMBO Molecular Medicine
                Publisher: John Wiley and Sons Inc. (Hoboken )
                ISSN (Print): 1757-4676
                ISSN (Electronic): 1757-4684
                Publication date (Electronic): 22 July 2019
                Publication date (Print): August 2019
                Volume: 11
                Issue: 8 ( doiID: 10.1002/emmm.v11.8 )
                Electronic Location Identifier: e9830
                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
                Author information
                https://orcid.org/0000-0002-6818-7225
                https://orcid.org/0000-0002-9795-0496
                Article
                Publisher ID: EMMM201809830
                DOI: 10.15252/emmm.201809830
                PMC ID: 6685082
                PubMed ID: 31328883
                SO-VID: 4a0d2221-1982-46b1-9bf5-2d36e8f1ff22
                Copyright © © 2019 The Authors. Published under the terms of the CC BY 4.0 license
                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.

                History
                Date received : 19 September 2018
                Date revision received : 28 June 2019
                Date accepted : 02 July 2019
                Page count
                Figures: 11, Tables: 0, Pages: 17, Words: 13817
                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
                Subject: Article
                Subject: Articles
                Custom metadata
                source-schema-version-number 2.0
                component-id emmm201809830
                cover-date August 2019
                details-of-publishers-convertor Converter:WILEY_ML3GV2_TO_NLMPMC version:5.6.7 mode:remove_FC converted:07.08.2019

                ScienceOpen disciplines: Molecular medicine
                Keywords: activin,medulloblastoma,smad2,smad3,tgfbeta,cancer
                Data availability:
                ScienceOpen disciplines: Molecular medicine
                Keywords: activin, medulloblastoma, smad2, smad3, tgfbeta, cancer

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