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 |
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| Authors: | Morgane Morabito, Magalie Larcher, Florence MG Cavalli, Chloé Foray, Antoine Forget, Liliana Mirabal‐Ortega, Mamy Andrianteranagna, Sabine Druillennec, Alexandra Garancher, Julien Masliah‐Planchon, Sophie Leboucher, Abel Debalkew, Alessandro Raso, Olivier Delattre, Stéphanie Puget, François Doz, Michael D Taylor, Olivier Ayrault, Franck Bourdeaut, Alain Eychène, Celio Pouponnot |
| Source: | EMBO Molecular Medicine, Vol 11, Iss 8, Pp 1-17 (2019) |
| Publisher Information: | Springer Nature, 2019. |
| Publication Year: | 2019 |
| Collection: | LCC:Medicine (General) LCC:Genetics |
| Subject Terms: | activin, medulloblastoma, Smad2, Smad3, TGFbeta, Medicine (General), R5-920, Genetics, QH426-470 |
| More Details: | 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. |
| Document Type: | article |
| File Description: | electronic resource |
| Language: | English |
| ISSN: | 1757-4676 1757-4684 14659743 |
| Relation: | https://doaj.org/toc/1757-4676; https://doaj.org/toc/1757-4684 |
| DOI: | 10.15252/emmm.201809830 |
| Access URL: | https://doaj.org/article/953a146597434510bae487e93455a269 |
| Accession Number: | edsdoj.953a146597434510bae487e93455a269 |
| Database: | Directory of Open Access Journals |
| ISSN: | 17574676 17574684 14659743 |
|---|---|
| DOI: | 10.15252/emmm.201809830 |
| Published in: | EMBO Molecular Medicine |
| Language: | English |