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.

mTORC1 promotes malignant large cell/ anaplastic histology and is a targetable vulnerability in SHH-TP53 mutant medulloblastoma / Conti, V.; Cominelli, M.; Pieri, V.; Gallotti, A. L.; Pagano, I.; Zanella, M.; Mazzoleni, S.; Pivetta, F.; Patane, M.; Scotti, G. M.; Piras, I. S.; Pollo, B.; Falini, A.; Zippo, A.; Castellano, A.; Maestro, R.; Poliani, P. L.; Galli, R.. - In: JCI INSIGHT. - ISSN 2379-3708. - ELETTRONICO. - 6:23(2021), pp. e15346201-e15346223. [10.1172/jci.insight.153462]

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

Zippo A.;
2021

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.
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Conti, V.; Cominelli, M.; Pieri, V.; Gallotti, A. L.; Pagano, I.; Zanella, M.; Mazzoleni, S.; Pivetta, F.; Patane, M.; Scotti, G. M.; Piras, I. S.; Pollo, B.; Falini, A.; Zippo, A.; Castellano, A.; Maestro, R.; Poliani, P. L.; Galli, R.
mTORC1 promotes malignant large cell/ anaplastic histology and is a targetable vulnerability in SHH-TP53 mutant medulloblastoma / Conti, V.; Cominelli, M.; Pieri, V.; Gallotti, A. L.; Pagano, I.; Zanella, M.; Mazzoleni, S.; Pivetta, F.; Patane, M.; Scotti, G. M.; Piras, I. S.; Pollo, B.; Falini, A.; Zippo, A.; Castellano, A.; Maestro, R.; Poliani, P. L.; Galli, R.. - In: JCI INSIGHT. - ISSN 2379-3708. - ELETTRONICO. - 6:23(2021), pp. e15346201-e15346223. [10.1172/jci.insight.153462]
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/11572/335260
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