Format

Send to

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

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

Author information

1
Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, 751 85 Uppsala, Sweden.
2
Wellcome Trust-MRC Stem Cell Institute, University of Cambridge, Tennis Court Road, Cambridge CB2 1QR, UK.
3
Tumor Initiation and Maintenance Program, NCI-Designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, 92037 La Jolla, CA, USA.
4
Department of Neuroscience, Karolinska Institutet, 171 77 Stockholm, Sweden.
5
Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, 751 85 Uppsala, Sweden. Electronic address: fredrik.swartling@igp.uu.se.

Abstract

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

Supplemental Content

Full text links

Icon for Elsevier Science Icon for PubMed Central
Loading ...
Support Center