Humanized Stem Cell Models of Pediatric Medulloblastoma Reveal an Oct4/mTOR Axis that Promotes Malignancy

Cell Stem Cell. 2019 Dec 5;25(6):855-870.e11. doi: 10.1016/j.stem.2019.10.005. Epub 2019 Nov 27.


Medulloblastoma (MB), the most frequent malignant childhood brain tumor, can arise from cellular malfunctions during hindbrain development. Here we generate humanized models for Sonic Hedgehog (SHH)-subgroup MB via MYCN overexpression in primary human hindbrain-derived neuroepithelial stem (hbNES) cells or iPSC-derived NES cells, which display a range of aggressive phenotypes upon xenografting. iPSC-derived NES tumors develop quickly with leptomeningeal dissemination, whereas hbNES-derived cells exhibit delayed tumor formation with less dissemination. Methylation and expression profiling show that tumors from both origins recapitulate hallmarks of infant SHH MB and reveal that mTOR activation, as a result of increased Oct4, promotes aggressiveness of human SHH tumors. Targeting mTOR decreases cell viability and prolongs survival, showing the utility of these varied models for dissecting mechanisms mediating tumor aggression and demonstrating the value of humanized models for a better understanding of pediatric cancers.

Keywords: MYCN; POU5F1; mTOR; medulloblastoma; metastasis; neuroepithelial stem cells; reprogramming.

MeSH terms

  • Animals
  • Cell Line
  • Cell Proliferation / genetics
  • Cell Proliferation / physiology
  • Cell Survival / genetics
  • Cell Survival / physiology
  • Female
  • Fluorescent Antibody Technique
  • Gene Expression Regulation, Neoplastic / genetics
  • Gene Expression Regulation, Neoplastic / physiology
  • Immunohistochemistry
  • Medulloblastoma / genetics
  • Medulloblastoma / metabolism*
  • Medulloblastoma / pathology*
  • Mice
  • Octamer Transcription Factor-3 / genetics
  • Octamer Transcription Factor-3 / metabolism*
  • Signal Transduction / genetics
  • Signal Transduction / physiology
  • Stem Cells / metabolism*
  • TOR Serine-Threonine Kinases / genetics
  • TOR Serine-Threonine Kinases / metabolism*


  • Octamer Transcription Factor-3
  • Pou5f1 protein, mouse
  • mTOR protein, mouse
  • TOR Serine-Threonine Kinases