Epidermal growth factor receptor and Ink4a/Arf: Convergent mechanisms governing terminal differentiation and transformation along the neural stem cell to astrocyte axis

Robert M. Bachoo, Elizabeth A. Maher, Keith L. Ligon, Norman E. Sharpless, Suzanne S. Chan, Mingjian James You, Yi Tang, Jessica DeFrances, Elizabeth Stover, Ralph Weissleder, David H. Rowitch, David N. Louis, Ronald A. DePinho

Research output: Contribution to journalArticlepeer-review

517 Scopus citations

Abstract

Ink4a/Arf inactivation and epidermal growth factor receptor (EGFR) activation are signature lesions in high-grade gliomas. How these mutations mediate the biological features of these tumors is poorly understood. Here, we demonstrate that combined loss of p16INK4a and p19ARF, but not of p53, p16INK4a, or p19ARF, enables astrocyte dedifferentiation in response to EGFR activation. Moreover, transduction of Ink4a/Arf-/- neural stem cells (NSCs) or astrocytes with constitutively active EGFR induces a common high-grade glioma phenotype. These findings identify NSCs and astrocytes as equally permissive compartments for gliomagenesis and provide evidence that p16INK4a and p19 ARF synergize to maintain terminal astrocyte differentiation. These data support the view that dysregulation of specific genetic pathways, rather than cell-of-origin, dictates the emergence and phenotype of high-grade gliomas.

Original languageEnglish (US)
Pages (from-to)269-277
Number of pages9
JournalCancer Cell
Volume1
Issue number3
DOIs
StatePublished - Apr 2002

ASJC Scopus subject areas

  • Oncology
  • Cell Biology
  • Cancer Research

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