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 (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 MBs developing in p53-deficient Ptch +/-SHH mice that, unexpectedly, showed LC/A traits that correlated with mechanistic Target Of Rapamycin Complex 1 (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 MBs and CSC-derived MBs resulted in reduced tumor burden and aggressiveness.Most remarkably, mTORC1 hyperactivation was detected only in p53-mutant SHH MB patients' 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.

Targeting mTOR Pathway in PTEN Deleted Newly Isolated Chordoma Cell Line

“…However, emerging evidence indicates that the deregulation of signaling pathways involving PI3K, Akt, PTEN, TSC1 or TSC2 may play a crucial role in chordomagenesis through the aberrant activation of the mTOR pathway [ 13 ]. mTOR is involved in the regulation of numerous cellular functions and mTOR hyperactivation is frequently observed in various types of cancers [ 20 ] contributing to cell proliferation, tumour initiation and progression [ 21 , 22 , 23 ]. Interestingly, chordomas have been reported in patients with tuberous sclerosis complex (TSC), a multisystem syndrome due to TSC1 or TSC2 alterations resulting in constitutive mTOR hyperactivation, suggesting an etiological role of TSC gene alterations in chordomagenesis [ 24 , 25 ].…”

Rewired Metabolism of Amino Acids and Its Roles in Glioma Pathology

“…Acetylated GLDC is prone to be degraded in the proteasomes and results in impaired pyrimidine synthesis and growth inhibition of gliomas [ 32 ]. Many glioma cells exhibit highly expressed mTORC1 and GLDC [ 32 , 33 ]. γ-Glutamylcyclotransferase (GGCT), one of the key enzymes promoting GSH synthesis, was demonstrated to be highly expressed in glioma cells.…”