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

Morgane Morabito (1, 2) , Magalie Larcher (2) , Florence M G Cavalli , Chloé Foray (2) , Antoine Forget (2) , Liliana Mirabal‐ortega (2) , Mamy Andrianteranagna (3, 4, 5) , Sabine Druillennec (2, 6) , Alexandra Garancher (2) , Julien Masliah‐planchon (3, 6) , Sophie Leboucher (7, 8) , Abel Debalkew , Alessandro Raso , Olivier Delattre (3) , Stéphanie Puget (9, 10) , François Doz (7) , Michael Taylor , Olivier Ayrault (11) , Franck Bourdeaut (3, 6) , Alain Eychène (2) , Celio Pouponnot (2, 6)

1 Department of Anatomy and Cell Biology [Montréal]
2 Signalisation normale et pathologique de l'embryon aux thérapies innovantes des cancers
3 U830 - Unité de génétique et biologie des cancers
4 CBIO - Centre de Bioinformatique
5 Cancer et génome: Bioinformatique, biostatistiques et épidémiologie d'un système complexe
6 PSL - Université Paris Sciences et Lettres
7 Institut Curie [Paris]
8 UP11 - Université Paris-Sud - Paris 11
9 UPD5 - Université Paris Descartes - Paris 5
10 Hôpital Necker - Enfants Malades [AP-HP]
11 SNC - Signalisation, neurobiologie et cancer - Signalisation cellulaire et neurobiologie

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.

Mots clés: activin; medulloblastoma; Smad2; Smad3; TGFbeta Subject Category Cancer

Domaines: Cancer; Neurobiologie; Génomique, Transcriptomique et Protéomique [q-bio.GN]

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⟩