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An autocrine ActivinB mechanism drives TGFβ/Activin signaling in Group 3 medulloblastoma
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 genomi...
Autores principales: | , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
John Wiley and Sons Inc.
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6685082/ https://www.ncbi.nlm.nih.gov/pubmed/31328883 http://dx.doi.org/10.15252/emmm.201809830 |
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author | Morabito, Morgane Larcher, Magalie Cavalli, Florence MG Foray, Chloé Forget, Antoine Mirabal‐Ortega, Liliana Andrianteranagna, Mamy Druillennec, Sabine Garancher, Alexandra Masliah‐Planchon, Julien Leboucher, Sophie Debalkew, Abel Raso, Alessandro Delattre, Olivier Puget, Stéphanie Doz, François Taylor, Michael D Ayrault, Olivier Bourdeaut, Franck Eychène, Alain Pouponnot, Celio |
author_facet | Morabito, Morgane Larcher, Magalie Cavalli, Florence MG Foray, Chloé Forget, Antoine Mirabal‐Ortega, Liliana Andrianteranagna, Mamy Druillennec, Sabine Garancher, Alexandra Masliah‐Planchon, Julien Leboucher, Sophie Debalkew, Abel Raso, Alessandro Delattre, Olivier Puget, Stéphanie Doz, François Taylor, Michael D Ayrault, Olivier Bourdeaut, Franck Eychène, Alain Pouponnot, Celio |
author_sort | Morabito, Morgane |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-6685082 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | John Wiley and Sons Inc. |
record_format | MEDLINE/PubMed |
spelling | pubmed-66850822019-08-12 An autocrine ActivinB mechanism drives TGFβ/Activin signaling in Group 3 medulloblastoma Morabito, Morgane Larcher, Magalie Cavalli, Florence MG Foray, Chloé Forget, Antoine Mirabal‐Ortega, Liliana Andrianteranagna, Mamy Druillennec, Sabine Garancher, Alexandra Masliah‐Planchon, Julien Leboucher, Sophie Debalkew, Abel Raso, Alessandro Delattre, Olivier Puget, Stéphanie Doz, François Taylor, Michael D Ayrault, Olivier Bourdeaut, Franck Eychène, Alain Pouponnot, Celio EMBO Mol Med Articles 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. John Wiley and Sons Inc. 2019-07-22 2019-08 /pmc/articles/PMC6685082/ /pubmed/31328883 http://dx.doi.org/10.15252/emmm.201809830 Text en © 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. |
spellingShingle | Articles Morabito, Morgane Larcher, Magalie Cavalli, Florence MG Foray, Chloé Forget, Antoine Mirabal‐Ortega, Liliana Andrianteranagna, Mamy Druillennec, Sabine Garancher, Alexandra Masliah‐Planchon, Julien Leboucher, Sophie Debalkew, Abel Raso, Alessandro Delattre, Olivier Puget, Stéphanie Doz, François Taylor, Michael D Ayrault, Olivier Bourdeaut, Franck Eychène, Alain Pouponnot, Celio An autocrine ActivinB mechanism drives TGFβ/Activin signaling in Group 3 medulloblastoma |
title | An autocrine ActivinB mechanism drives TGFβ/Activin signaling in Group 3 medulloblastoma |
title_full | An autocrine ActivinB mechanism drives TGFβ/Activin signaling in Group 3 medulloblastoma |
title_fullStr | An autocrine ActivinB mechanism drives TGFβ/Activin signaling in Group 3 medulloblastoma |
title_full_unstemmed | An autocrine ActivinB mechanism drives TGFβ/Activin signaling in Group 3 medulloblastoma |
title_short | An autocrine ActivinB mechanism drives TGFβ/Activin signaling in Group 3 medulloblastoma |
title_sort | autocrine activinb mechanism drives tgfβ/activin signaling in group 3 medulloblastoma |
topic | Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6685082/ https://www.ncbi.nlm.nih.gov/pubmed/31328883 http://dx.doi.org/10.15252/emmm.201809830 |
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