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.
Highlights
Medulloblastoma (MB) is one of the most common malignant brain tumors of children, thought to originate from distinct neural stem/progenitor cell populations of the cerebellum during early embryonic development (1) (2)
Key molecular alterations identified in MB subgroups have inferred the development of novel biomarkers that were confirmed in the fifth edition of the World Health Organization (WHO) Classification of Tumors of the Central Nervous System (WHO CNS5), which classifies MBs based on their histological appearance and on their molecular features and identifies four molecular variants of the disease (WNT, sonic hedgehog (SHH)-TP53 wild type, SHH-TP53 mutant, and non-WNT/non-SHH, the latter including both Group 3 and 4 MBs) (6) (7)
By taking advantage of subgroup-specific SHH, WNT and Group 3 mouse cancer stem cell (CSC) lines that others and we isolated by the NeuroSphere assay from different subtypes of mouse MBs (17) (18) (25) (26), we report for the first time that mechanistic Target Of Rapamycin (mTOR) hyperactivation in MB is causally and involved in the acquisition of large cell/anaplastic (LC/A) histology and in increased malignancy in a specific subset of human SHH MBs and that addiction to this pathway in these patients may represent a cancer-specific vulnerability to be taken advantage of therapeutically
Summary
Medulloblastoma (MB) is one of the most common malignant brain tumors of children, thought to originate from distinct neural stem/progenitor cell populations of the cerebellum during early embryonic development (1) (2). Key molecular alterations identified in MB subgroups have inferred the development of novel biomarkers that were confirmed in the fifth edition of the World Health Organization (WHO) Classification of Tumors of the Central Nervous System (WHO CNS5), which classifies MBs based on their histological appearance and on their molecular features and identifies four molecular variants of the disease (WNT, SHH-TP53 wild type, SHH-TP53 mutant, and non-WNT/non-SHH, the latter including both Group 3 and 4 MBs) (6) (7). WNT subgroup patients have an excellent prognosis, whereas Group 3 patients have a substantially worse prognosis (3) (8) (9).
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