An autocrine ActivinB mechanism drives TGF β/Activin signaling in Group 3 medulloblastoma - Archive ouverte HAL Access content directly
Journal Articles EMBO Molecular Medicine Year : 2019

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

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Florence M G Cavalli
  • Function : Author
Abel Debalkew
  • Function : Author
Alessandro Raso
  • Function : Author
Michael Taylor
  • Function : Author
Olivier Ayrault

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 TGFb/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 TGFb/Activin pathway is active in a subset of Group 3 MB and can be therapeutically targeted.
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Dates and versions

hal-02347105 , version 1 (05-11-2019)

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Morgane Morabito, Magalie Larcher, Florence M G Cavalli, Chloé Foray, Antoine Forget, et al.. An autocrine ActivinB mechanism drives TGF β/Activin signaling in Group 3 medulloblastoma. EMBO Molecular Medicine, 2019, 6, pp.e9830. ⟨10.15252/emmm.201809830⟩. ⟨hal-02347105⟩
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