A Tumor Suppressor Function for Notch Signaling in Forebrain Tumor Subtypes

Paper URL: Science Direct

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-Jk, 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 sub- types, increased patient survival, and lower tumor grade. Additionally, simultaneous inactivation of RBP- Jk 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 tumours.

Key Findings

• Notch signaling and p53 cooperate to reduce initiation of forebrain tumor subtypes

• Anti-tumorigenic effects of Notch are linked to regulation of quiescence

• Inhibiting Notch promotes a primitive neuroectodermal-like tumor fate

• Low Notch activity correlates with poor prognosis for patients with glioma subtypes