A Tumor Suppressor Function for Notch Signaling in Forebrain Tumor Subtypes

Claudio Giachino, Jean Louis Boulay, Robert Ivanek, Alvaro Alvarado, Cristobal Tostado, Sebastian Lugert, Jan Tchorz, Mustafa Coban, Luigi Mariani, Bernhard Bettler, Justin Lathia, Stephan Frank, Stefan Pfister, Marcel Kool, Verdon Taylor

Research output: Contribution to journalArticlepeer-review

72 Citations (Scopus)

Abstract

In the brain, Notch signaling maintains normal neural stem cells, but also brain cancer stem cells, indicating an oncogenic role. Here, we identify an unexpected tumor suppressor function for Notch in forebrain tumor subtypes. Genetic inactivation of RBP-Jκ, a key Notch mediator, or Notch1 and Notch2 receptors accelerates PDGF-driven glioma growth in mice. Conversely, genetic activation of the Notch pathway reduces glioma growth and increases survival. In humans, high Notch activity strongly correlates with distinct glioma subtypes, increased patient survival, and lower tumor grade. Additionally, simultaneous inactivation of RBP-Jκ and p53 induces primitive neuroectodermal-like tumors in mice. Hence, Notch signaling cooperates with p53 to restrict cell proliferation and tumor growth in mouse models of human brain tumors.

Original languageEnglish
Pages (from-to)730-742
Number of pages13
JournalCancer Cell
Volume28
Issue number6
DOIs
Publication statusPublished - 14 Dec 2015
Externally publishedYes

Keywords

  • Brain tumor
  • Glioma
  • Hes5
  • Notch signaling
  • Primitive neuroectodermal tumor

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