TY - JOUR AU - Conti, Valentina AU - Cominelli, Manuela AU - Pieri, Valentina AU - Gallotti, Alberto L. AU - Pagano, Ilaria AU - Zanella, Matteo AU - Mazzoleni, Stefania AU - Pivetta, Flavia AU - Patanè, Monica AU - Scotti, Giulia M. AU - Piras, Ignazio S. AU - Pollo, Bianca AU - Falini, Andrea AU - Zippo, Alessio AU - Castellano, Antonella AU - Maestro, Roberta AU - Poliani, Pietro L. AU - Galli, Rossella T1 - mTORC1 promotes malignant large cell/anaplastic histology and is a targetable vulnerability in SHH-TP53 mutant medulloblastoma PY - 2021/12/08/ AB - Medulloblastoma (MB), one of the most malignant brain tumors of childhood, comprises distinct molecular subgroups, with p53 mutant sonic hedgehog–activated (SHH-activated) MB patients having a very severe outcome that is associated with unfavorable histological large cell/anaplastic (LC/A) features. To identify the molecular underpinnings of this phenotype, we analyzed a large cohort of MB developing in p53-deficient Ptch+/– SHH mice that, unexpectedly, showed LC/A traits that correlated with mTORC1 hyperactivation. Mechanistically, mTORC1 hyperactivation was mediated by a decrease in the p53-dependent expression of mTORC1 negative regulator Tsc2. Ectopic mTORC1 activation in mouse MB cancer stem cells (CSCs) promoted the in vivo acquisition of LC/A features and increased malignancy; accordingly, mTORC1 inhibition in p53-mutant Ptch+/– SHH MB and CSC-derived MB resulted in reduced tumor burden and aggressiveness. Most remarkably, mTORC1 hyperactivation was detected only in p53-mutant SHH MB patient samples, and treatment with rapamycin of a human preclinical model phenocopying this subgroup decreased tumor growth and malignancy. Thus, mTORC1 may act as a specific druggable target for this subset of SHH MB, resulting in the implementation of a stringent risk stratification and in the potentially rapid translation of this precision medicine approach into the clinical setting. JF - JCI Insight JA - JCI Insight SN - 2379-3708 DO - 10.1172/jci.insight.153462 VL - 6 IS - 23 UR - https://doi.org/10.1172/jci.insight.153462 PB - The American Society for Clinical Investigation ER -