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 1

Autochthonous MB developing in Ptch1+/– p53–/– mice show large cell/anaplastic histopathological features that are associated with mTORC1 hyperactivation.

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Autochthonous MB developing in Ptch1+/– p53–/– mice show large cell/anap...
(A) Typical features of desmoplastic MB (e.g., small undifferentiated cells interspersed in a dense neuropil) and of classic MB (e.g., small “blue” cells with round/ovoid nuclei) are found in HW MB (H&E). Conversely, histomorphological LC/A characteristics are observed in HN MB. Scale bars: 50 μm. Traits typical of the large cell variant, as cells with round nuclei with prominent nuclei (white arrows), and of the anaplastic variant, as angular nuclei, nuclear wrapping (white arrowhead), nuclear molding, and frequent apoptotic and mitotic cells (white arrowheads), are detected in all HN MB. Scale bars: 10 μm. (B) Higher numbers of cells hyperactivating pS6 (cytoplasmic staining, brown) are found in HN LC/A MB than in HW MB. The few pS6-IR cells (cytoplasmic staining, blue) in HW MB are stromal cells, positive for the macrophage/microglia marker IRF8 (nuclear staining, brown). Conversely, most pS6-IR cells in HN MB (cytoplasmic staining, blue) are tumor cells that do not express IRF8 (nuclear staining, brown). Increased activation of p4EBP1 is observed in HN MB (cytoplasmic staining, brown). Scale bars: 50 μm; insets: 10 μm. (C) Quantification of marker expression (shown as arbitrary units) and of cell subpopulations (shown as number of cells in a 60× microscopic field) is shown in the graphs. pS6+IRF8– cells in HW versus HN MB: ***P < 0.005, ****P < 0.0001, Student’s t test, unpaired. (D) Increased c-Myc expression (nuclear staining, brown) is detected in HN MB, with some c-Myc+ cells being also pS6-IR (cytoplasmic, blue; insets). mTORC1-regulated gene Gpnmb (cytoplasmic staining, brown) is upregulated in HN MB. Scale bars: 50 μm; insets: 10 μm. (E) Quantification of marker expression is shown in the graphs. **P < 0.01, ****P < 0.0001. 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 < 0.01; ***P < 0.005; ****P < 0.001.