Seminar – Irene Basili

Invited by the Institut Jacques Monod, Irene Basili will present a seminar on the theme:

AMBRA1 controls the Sonic Hedgehog signaling pathway and SHH-medulloblastoma

Abstract:

AMBRA1 (Autophagy and Beclin 1 Regulator 1) is primarily recognized as a tumor suppressor, however its role as a tumor promoter has garnered increasing attention. Here, leveraging clinical data of an international multi-omic medulloblastoma (MB) cohort, we identified that elevated AMBRA1 protein levels, independently of its mRNA expression, correlate with poor prognosis in the Sonic Hedgehog subgroup (MBSHH) compared to other MB variants. Mechanistically, AMBRA1 enhances SHH signaling by stabilizing GLI1, the pathway’s final effector, via inhibition of its βTrCP-mediated degradation. Additionally, AMBRA1 protein stability is modulated by the REN E3 ubiquitin ligase, a tumor suppressor gene lost in MBSHH. Inhibition of AMBRA1 blocks MBSHH growth in murine and patient-derived pre-clinical models, highlighting its therapeutic potential. Moreover, combining AMBRA1 knockdown with FDA-approved SHH inhibitors enhances antitumor efficacy. These findings identify the AMBRA1/βTrCP/REN axis as a key regulatory mechanism in SHH signaling and discover an unrecognized function of AMBRA1 in MBSHH, providing actionable insights for innovative targeted therapies.

This seminar is part of the Paris Postdoc seminar series.