Humanized Stem Cell Models of Pediatric Medulloblastoma Reveal an Oct4/mTOR Axis that Promotes Malignancy.
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
MYCN
POU5F1
mTOR
medulloblastoma
metastasis
neuroepithelial stem cells
reprogramming
Journal
Cell stem cell
ISSN: 1875-9777
Titre abrégé: Cell Stem Cell
Pays: United States
ID NLM: 101311472
Informations de publication
Date de publication:
05 Dec 2019
05 Dec 2019
Historique:
received:
19
07
2018
revised:
26
06
2019
accepted:
18
10
2019
pubmed:
2
12
2019
medline:
15
9
2020
entrez:
2
12
2019
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 31786016
pii: S1934-5909(19)30426-6
doi: 10.1016/j.stem.2019.10.005
pmc: PMC6900751
pii:
doi:
Substances chimiques
Octamer Transcription Factor-3
0
Pou5f1 protein, mouse
0
mTOR protein, mouse
EC 2.7.1.1
TOR Serine-Threonine Kinases
EC 2.7.11.1
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
855-870.e11Subventions
Organisme : Wellcome Trust
Pays : United Kingdom
Organisme : Wellcome Trust
ID : 201511/Z/16/Z
Pays : United Kingdom
Organisme : European Research Council
ID : 640275
Pays : International
Informations de copyright
Copyright © 2019 The Author(s). Published by Elsevier Inc. All rights reserved.
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