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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...

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Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2019
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.
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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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