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 7

Pharmacological targeting of the mTOR pathway significantly impairs the growth of CSC-derived mTOR–driven LC/A MB but not that of MB belonging to other subgroups.

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Pharmacological targeting of the mTOR pathway significantly impairs the ...
(A) Tumor growth is significantly reduced by rapamycin treatment in LC/A tumors generated by HN CSCs with endogenous activation of mTORC1 (L83 and L66, 28 days of treatment for both vehicle and rapamycin arms; n = 11), the same CSCs transduced with RhebQ64L (L83, 25 days of treatment for both vehicle and rapamycin arms; n = 5), and classic HH CSCs transduced with RhebQ64L (17 days of treatment for vehicle arm; 30 days of treatment for rapamycin arm; n = 6). Conversely, tumor growth was only slightly affected by rapamycin treatment in classic tumors generated by classic HH CSCs (LB, 30 days of treatment for both vehicle and rapamycin arms; n = 6). No significant differences in tumor volume were detected in LC/A tumors induced by HH CSCs with no endogenous hyperactivation of mTORC1 (L84, 40 days of treatment for both vehicle and rapamycin arms; n = 5) and MycT58A-transduced CSCs (ML9, 20 days of treatment for both vehicle and rapamycin arms; n = 6). (B) H&E analysis following rapamycin treatment of the different types of LC/A MB shows a significant reduction in nuclear pleomorphism (insets in mTOR-driven LC/A MB, left panels), in nuclear molding and in cell size (middle and right panels). Activation of both pS6 and pNdrg1 was strongly decreased by treatment, and so was the expression of Gpnmb, Yap1, and Sox2. All scale bars: 50 μm. Quantitative data are represented as a box-and-whisker plot, with bounds from 25th to 75th percentile, median line, and whiskers ranging from minimum to maximum values. Student’s t test, unpaired. *P < 0.05; **P < 0.01; ***P < 0.005.