An autocrine ActivinB mechanism drives TGFß/Activin signaling in Group 3 medulloblastoma.
EMBO Mol Med
; 11(8): e9830, 2019 08.
Article
em En
| MEDLINE
| ID: mdl-31328883
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 TGFß/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 TGFß/Activin pathway is active in a subset of Group 3 MB and can be therapeutically targeted.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Neoplasias Cerebelares
/
Fator de Crescimento Transformador beta
/
Comunicação Autócrina
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Subunidades beta de Inibinas
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Fator de Crescimento Transformador beta1
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Fator de Crescimento Transformador beta3
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Meduloblastoma
Tipo de estudo:
Prognostic_studies
Limite:
Animals
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Female
/
Humans
Idioma:
En
Revista:
EMBO Mol Med
Assunto da revista:
BIOLOGIA MOLECULAR
Ano de publicação:
2019
Tipo de documento:
Article
País de afiliação:
França