Stalled Developmental Programs at the Root of Pediatric Brain Tumors

Overview

Journal Nat Genet

Specialty Genetics

Date 2019 Nov 27

PMID 31768071

Citations 110

Authors

Selin Jessa

Alexis Blanchet-Cohen

Brian Krug

Maria Vladoiu

Marie Coutelier

Damien Faury

Brice Poreau

Nicolas De Jay

Steven Hebert

Jean Monlong

W Todd Farmer

Laura K Donovan

Yixing Hu

Melissa K McConechy

Florence M G Cavalli

Leonie G Mikael

Benjamin Ellezam

Maxime Richer

Andrea Allaire

Alexander G Weil

Jeffrey Atkinson

Jean-Pierre Farmer

Roy W R Dudley

Valerie Larouche

Louis Crevier

Steffen Albrecht

Mariella G Filbin

Herve Sartelet

Pierre-Eric Lutz

Corina Nagy

Gustavo Turecki

Santiago Costantino

Peter B Dirks

Keith K Murai

Guillaume Bourque

Jiannis Ragoussis

Livia Garzia

Michael D Taylor

Nada Jabado

Claudia L Kleinman

Affiliations

Soon will be listed here.

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.

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