mTORC1 promotes malignant large cell/anaplastic histology and is a targetable vulnerability in SHH-TP53 mutant medulloblastoma
Valentina Conti, … , Pietro L. Poliani, Rossella Galli
Valentina Conti, … , Pietro L. Poliani, Rossella Galli
Published October 21, 2021
Citation Information: JCI Insight. 2021;6(23):e153462. https://doi.org/10.1172/jci.insight.153462.
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Research Article Neuroscience Oncology

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

Abstract

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.

Authors

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

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Figure 6

Pharmacological targeting of the mTOR pathway hampers the growth of autochthonous SHH-TP53 mutant MB.

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Pharmacological targeting of the mTOR pathway hampers the growth of auto...
(A) Longitudinal T2-weighted MRI analysis indicates that rapamycin administration significantly impairs the growth of early- and late-stage HN MB. (B) MB volume, as calculated by binary masks at day 55 of age — i.e., the MRI time point closer to the median survival of control mice — is significantly reduced by both rapamycin treatment regimens when compared with vehicle-treated controls (late-treated HN MB, *P <0.05; early-treated HN MB, **P <0.01). At the latest time points assessed for early (90 days) and late-treated (70 days) HN MB, both treated HN MB are significantly smaller than controls at 55 days. Statistical analysis is shown in the upper right table. (C) Kaplan-Meier survival curves show that the lifespan of HN mice treated with rapamycin at early and late stages of tumor development is significantly increased as compared with control mice (n = 11 for vehicle-treated mice, n = 5 for early-treated mice, n = 7 for late-treated mice). (D) Following late rapamycin treatment, HN MB show a significant reduction in the activation of pS6, but not of p4EBP1, in nuclear pleomorphism and molding, as well as in Yap1, N-Myc, and Gli2 expression. All scale bars: 50 μm. See Supplemental Figure 8 for detailed statistical analysis. Quantitative data are presented as floating bars from minimum to maximum values, line at mean. One-way ANOVA, followed by Dunnett’s multiple comparison test (B), and log rank test (C). *P < 0.05; **P < 0.01.