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). 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 preclinical models. 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 into brain tumor biology.
AMBRA1 enhances Sonic Hedgehog signaling during cerebellar development and in medulloblastoma / Basili, Irene; Bufalieri, Francesca; Conenna, Marilisa; Navacci, Shirin; Li, Yue-Ru; Torrejon, Jacob; Bernardi, Flavia; Lospinoso Severini, Ludovica; Marsaud, Veronique; Cancila, Gabriele; Bourmeau, Guillaume; Yu, Hua; Lo Re, Valentina; Talbot, Julie; Adabbo, Gennaro; Di Pinto, Alberico; Agnoli, Francesca; Giovannini, Daniela; Leonardi, Simona; Bordone, Rosa; Petroni, Marialaura; Souphron, Judith; Blauwblomme, Thomas; Beccaria, Kévin; Dufour, Christelle; D'Angelo, Luca; De Smaele, Enrico; Canettieri, Gianluca; Giannini, Giuseppe; Fimia, Gian Maria; Maroder, Marella; Guardavaccaro, Daniele; Pazzaglia, Simonetta; Tsai, Jin-Wu; Infante, Paola; Ayrault, Olivier; Di Marcotullio, Lucia. - In: DEVELOPMENTAL CELL. - ISSN 1534-5807. - (2026). [10.1016/j.devcel.2026.03.008]
AMBRA1 enhances Sonic Hedgehog signaling during cerebellar development and in medulloblastoma
Basili, Irene;Bufalieri, Francesca;Conenna, Marilisa;Navacci, Shirin;Lospinoso Severini, Ludovica;Adabbo, Gennaro;Di Pinto, Alberico;Agnoli, Francesca;Bordone, Rosa;Petroni, Marialaura;De Smaele, Enrico;Canettieri, Gianluca;Giannini, Giuseppe;Fimia, Gian Maria;Maroder, Marella;Infante, Paola;Di Marcotullio, Lucia
2026
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). 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 preclinical models. 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 into brain tumor biology.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
