JCI Insight (Dec 2021)

mTORC1 promotes malignant large cell/anaplastic histology and is a targetable vulnerability in SHH-TP53 mutant medulloblastoma

  • Valentina Conti,
  • Manuela Cominelli,
  • Valentina Pieri,
  • Alberto L. Gallotti,
  • Ilaria Pagano,
  • Matteo Zanella,
  • Stefania Mazzoleni,
  • Flavia Pivetta,
  • Monica Patanè,
  • Giulia M. Scotti,
  • Ignazio S. Piras,
  • Bianca Pollo,
  • Andrea Falini,
  • Alessio Zippo,
  • Antonella Castellano,
  • Roberta Maestro,
  • Pietro L. Poliani,
  • Rossella Galli

Journal volume & issue
Vol. 6, no. 23

Abstract

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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.

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