Go to The Journal of Clinical Investigation
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Transfers
  • Advertising
  • Job board
  • Contact
  • Current issue
  • Past issues
  • By specialty
    • COVID-19
    • Cardiology
    • Immunology
    • Metabolism
    • Nephrology
    • Oncology
    • Pulmonology
    • All ...
  • Videos
  • Collections
    • Resource and Technical Advances
    • Clinical Medicine
    • Reviews
    • Editorials
    • Perspectives
    • Top read articles
  • JCI This Month
    • Current issue
    • Past issues

  • Current issue
  • Past issues
  • Specialties
  • In-Press Preview
  • Editorials
  • Viewpoint
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Transfers
  • Advertising
  • Job board
  • Contact
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.
View: Text | PDF
Research Article Neuroscience Oncology

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

  • Text
  • PDF
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

×

Figure 4

HN MB-derived CSCs give rise to LC/A MB that hyperactivate mTORC1.

Options: View larger image (or click on image) Download as PowerPoint

HN MB-derived CSCs give rise to LC/A MB that hyperactivate mTORC1.
(A) ...
(A) Western blot analysis shows significantly higher pS6 activation and lower Myc expression in HN CSC lines than in HH and MycT58A CSC lines. (B) Western blot analysis shows significantly higher pS6 activation and, on average, lower Myc expression in tumors derived from the implantation of HN CSC lines compared with those from HH and MycT58A CSCs. (C) H&E staining showing classic features in HH CSC–derived MB, such as small cells intermingled with extensive neuropil (CSC line LB). Tumors from a subset of HH (CSC line L84) and from MycT58A CSC lines (CSC line ML9) are endowed with LC/A characteristics, such as nuclear molding, prominent nucleoli, and apoptosis; in both cases, pS6-IR cells are few (cytoplasmic staining, brown) and are double-labeled with IRF8, indicating that they are tumor stromal cells (pS6, cytoplasmic staining, blue; IRF8, nuclear staining, brown). c-Myc (nuclear staining, brown) is lowly expressed in classic HH CSC–derived tumors, whereas it is very highly expressed in LC/A tumors derived from a subset of HH (CSC line L84) and from MycT58A CSC lines (CSC line ML9). All scale bars: 50 μm. (D) Tumors from HN CSCs (CSC lines L83 and L66) show LC/A traits, such as increased nuclear pleomorphism, presence of large cells, and high level of cellular atypia. pS6 is hyperactivated in tumor cells (cytoplasmic staining, brown), as demonstrated by the absence of colabeling of pS6+ cells (cytoplasmic staining, blue) with IRF8 (nuclear staining, brown). c-Myc expression is found in medium-to-high number of cells. All scale bars: 50 μm. (E) Quantification of the level of marker expression is shown in the graphs. Quantitative data are presented as floating bars from minimum to maximum values, line at mean. One-way ANOVA followed by Tukey’s multiple comparison test. See Supplemental Table 5 for detailed statistical analysis.

Copyright © 2023 American Society for Clinical Investigation
ISSN 2379-3708

Sign up for email alerts