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

Čančer, Matko ; Hutter, Sonja ; Holmberg, Karl O ; Rosén, Gabriela ; Sundström, Anders ; Tailor, Jignesh ; Bergström, Tobias ; Garancher, Alexandra ; Essand, Magnus and Wechsler-Reya, Robert J , et al. (2019) In Cell Stem Cell 25(6). p.855-870
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... (More)

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.

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publishing date
type
Contribution to journal
publication status
published
subject
keywords
Animals, Cell Line, Cell Proliferation/genetics, Cell Survival/genetics, Female, Fluorescent Antibody Technique, Gene Expression Regulation, Neoplastic/genetics, Immunohistochemistry, Medulloblastoma/genetics, Mice, Octamer Transcription Factor-3/genetics, Signal Transduction/genetics, Stem Cells/metabolism, TOR Serine-Threonine Kinases/genetics
in
Cell Stem Cell
volume
25
issue
6
pages
27 pages
publisher
Cell Press
external identifiers
  • pmid:31786016
  • scopus:85075575203
ISSN
1934-5909
DOI
10.1016/j.stem.2019.10.005
language
English
LU publication?
no
id
ef3b8584-a433-4764-8865-e417872182ab
date added to LUP
2021-08-09 14:42:27
date last changed
2024-06-15 13:57:06
@article{ef3b8584-a433-4764-8865-e417872182ab,
  abstract     = {{<p>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.</p>}},
  author       = {{Čančer, Matko and Hutter, Sonja and Holmberg, Karl O and Rosén, Gabriela and Sundström, Anders and Tailor, Jignesh and Bergström, Tobias and Garancher, Alexandra and Essand, Magnus and Wechsler-Reya, Robert J and Falk, Anna and Weishaupt, Holger and Swartling, Fredrik J}},
  issn         = {{1934-5909}},
  keywords     = {{Animals; Cell Line; Cell Proliferation/genetics; Cell Survival/genetics; Female; Fluorescent Antibody Technique; Gene Expression Regulation, Neoplastic/genetics; Immunohistochemistry; Medulloblastoma/genetics; Mice; Octamer Transcription Factor-3/genetics; Signal Transduction/genetics; Stem Cells/metabolism; TOR Serine-Threonine Kinases/genetics}},
  language     = {{eng}},
  month        = {{12}},
  number       = {{6}},
  pages        = {{855--870}},
  publisher    = {{Cell Press}},
  series       = {{Cell Stem Cell}},
  title        = {{Humanized Stem Cell Models of Pediatric Medulloblastoma Reveal an Oct4/mTOR Axis that Promotes Malignancy}},
  url          = {{https://lup.lub.lu.se/search/files/101033579/Humanized_Stem_Cell_Models.pdf}},
  doi          = {{10.1016/j.stem.2019.10.005}},
  volume       = {{25}},
  year         = {{2019}},
}