Humanized Stem Cell Models of Pediatric Medulloblastoma Reveal an Oct4/mTOR Axis that Promotes Malignancy
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) c...
Saved in:
Published in | Cell stem cell Vol. 25; no. 6; pp. 855 - 870.e11 |
---|---|
Main Authors | , , , , , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
United States
Elsevier Inc
05.12.2019
Cell Press |
Subjects | |
Online Access | Get full text |
Cover
Loading…
Summary: | 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.
[Display omitted]
•Human iPSC-derived or primary neuroepithelial stem cells can be transformed by MYCN•MYCN drives infant SHH medulloblastoma with clinically relevant features•Epigenetically regulated Oct4 promotes mTOR hyperactivation in infant SHH tumors•mTOR inhibition efficiently targets metastatic SHH medulloblastoma models and PDXs
Čančer et al. report multiple models of infant Shh medulloblastoma; human iPSC-derived models display significant malignancy, whereas primary hindbrain neuroepithelial stem cell-derived models are less aggressive. These models were used to identify a role for Oct4 in promoting mTOR activation in metastatic tumors, which were sensitive to mTOR inhibition. |
---|---|
Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Lead Contact |
ISSN: | 1934-5909 1875-9777 1875-9777 |
DOI: | 10.1016/j.stem.2019.10.005 |