Stalled developmental programs at the root of pediatric brain tumors.

TitleStalled developmental programs at the root of pediatric brain tumors.
Publication TypeJournal Article
Year of Publication2019
AuthorsJessa S, Blanchet-Cohen A, Krug B, Vladoiu M, Coutelier M, Faury D, Poreau B, De Jay N, Hébert S, Monlong J, W Farmer T, Donovan LK, Hu Y, McConechy MK, Cavalli FMG, Mikael LG, Ellezam B, Richer M, Allaire A, Weil AG, Atkinson J, Farmer J-P, Dudley RWR, Larouche V, Crevier L, Albrecht S, Filbin MG, Sartelet H, Lutz P-E, Nagy C, Turecki G, Costantino S, Dirks PB, Murai KK, Bourque G, Ragoussis J, Garzia L, Taylor MD, Jabado N, Kleinman CL
JournalNat Genet
Volume51
Issue12
Pagination1702-1713
Date Published2019 Dec
ISSN1546-1718
Abstract

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.

DOI10.1038/s41588-019-0531-7
Alternate JournalNat. Genet.
PubMed ID31768071
PubMed Central IDPMC6885128
Grant ListP01 CA196539 / CA / NCI NIH HHS / United States
R01 CA148699 / CA / NCI NIH HHS / United States
R01 CA159859 / CA / NCI NIH HHS / United States