Stalled developmental programs at the root of pediatric brain tumors.
Fiche publication
Date publication
décembre 2019
Journal
Nature genetics
Auteurs
Membres identifiés du Cancéropôle Est :
Dr LUTZ Pierre-Eric
Tous les auteurs :
Jessa S, Blanchet-Cohen A, Krug B, Vladoiu M, Coutelier M, Faury D, Poreau B, De Jay N, Hébert S, Monlong J, Farmer WT, Donovan LK, Hu Y, McConechy MK, Cavalli FMG, Mikael LG, Ellezam B, Richer M, Allaire A, Weil AG, Atkinson J, Farmer JP, Dudley RWR, Larouche V, Crevier L, Albrecht S, Filbin MG, Sartelet H, Lutz PE, Nagy C, Turecki G, Costantino S, Dirks PB, Murai KK, Bourque G, Ragoussis J, Garzia L, Taylor MD, Jabado N, Kleinman CL
Lien Pubmed
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.
Mots clés
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
Référence
Nat Genet. 2019 12;51(12):1702-1713