Stalled developmental programs at the root of pediatric brain tumors.
Animals
Brain
/ embryology
Brain Neoplasms
/ genetics
Cell Line, Tumor
Gene Expression Regulation, Developmental
Humans
Infant
Medulloblastoma
/ genetics
Mice
Neoplasms, Germ Cell and Embryonal
/ genetics
Nerve Fibers
/ pathology
Prosencephalon
/ cytology
Rhabdoid Tumor
/ genetics
Single-Cell Analysis
Journal
Nature genetics
ISSN: 1546-1718
Titre abrégé: Nat Genet
Pays: United States
ID NLM: 9216904
Informations de publication
Date de publication:
12 2019
12 2019
Historique:
received:
31
01
2019
accepted:
18
10
2019
pubmed:
27
11
2019
medline:
18
1
2020
entrez:
27
11
2019
Statut:
ppublish
Résumé
Childhood brain tumors have suspected prenatal origins. To identify vulnerable developmental states, we generated a single-cell transcriptome atlas of >65,000 cells from embryonal pons and forebrain, two major tumor locations. We derived signatures for 191 distinct cell populations and defined the regional cellular diversity and differentiation dynamics. Projection of bulk tumor transcriptomes onto this dataset shows that WNT medulloblastomas match the rhombic lip-derived mossy fiber neuronal lineage and embryonal tumors with multilayered rosettes fully recapitulate a neuronal lineage, while group 2a/b atypical teratoid/rhabdoid tumors may originate outside the neuroectoderm. Importantly, single-cell tumor profiles reveal highly defined cell hierarchies that mirror transcriptional programs of the corresponding normal lineages. Our findings identify impaired differentiation of specific neural progenitors as a common mechanism underlying these pediatric cancers and provide a rational framework for future modeling and therapeutic interventions.
Identifiants
pubmed: 31768071
doi: 10.1038/s41588-019-0531-7
pii: 10.1038/s41588-019-0531-7
pmc: PMC6885128
mid: NIHMS1541331
doi:
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1702-1713Subventions
Organisme : NCI NIH HHS
ID : P01 CA196539
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA148699
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA159859
Pays : United States
Organisme : CIHR
Pays : Canada
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