Stalled developmental programs at the root of pediatric brain tumors

Nat Genet. 2019 Dec;51(12):1702-1713. doi: 10.1038/s41588-019-0531-7. Epub 2019 Nov 25.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Brain / embryology*
  • Brain / pathology
  • Brain Neoplasms / genetics*
  • Brain Neoplasms / pathology*
  • Cell Line, Tumor
  • Gene Expression Regulation, Developmental*
  • Humans
  • Infant
  • Medulloblastoma / genetics
  • Medulloblastoma / pathology
  • Mice
  • Neoplasms, Germ Cell and Embryonal / genetics
  • Neoplasms, Germ Cell and Embryonal / pathology
  • Nerve Fibers / pathology
  • Nerve Fibers / physiology
  • Prosencephalon / cytology
  • Prosencephalon / embryology
  • Rhabdoid Tumor / genetics
  • Rhabdoid Tumor / pathology
  • Single-Cell Analysis