A Tumor Suppressor Function for Notch Signaling in Forebrain Tumor Subtypes

• Published in: Cancer cell Vol. 28; no. 6; pp. 730 - 742
• Main Authors: Giachino, Claudio, Boulay, Jean-Louis, Ivanek, Robert, Alvarado, Alvaro, Tostado, Cristobal, Lugert, Sebastian, Tchorz, Jan, Coban, Mustafa, Mariani, Luigi, Bettler, Bernhard, Lathia, Justin, Frank, Stephan, Pfister, Stefan, Kool, Marcel, Taylor, Verdon
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 14-12-2015
• Subjects: Animals; Basic Helix-Loop-Helix Transcription Factors - genetics; Basic Helix-Loop-Helix Transcription Factors - metabolism; Brain Neoplasms - genetics; Brain Neoplasms - metabolism; Brain Neoplasms - mortality; Brain Neoplasms - pathology; brain tumor; Cell Proliferation; Databases, Genetic; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Gene Transfer Techniques; glioma; Glioma - genetics; Glioma - metabolism; Glioma - mortality; Glioma - pathology; Hes5; Humans; Immunoglobulin J Recombination Signal Sequence-Binding Protein - genetics; Immunoglobulin J Recombination Signal Sequence-Binding Protein - metabolism; Infusions, Intraventricular; Kaplan-Meier Estimate; Mice, Knockout; Neoplasm Grading; Neoplastic Stem Cells - metabolism; Neoplastic Stem Cells - pathology; Neural Stem Cells - metabolism; Neural Stem Cells - pathology; Notch signaling; Phenotype; Platelet-Derived Growth Factor - administration & dosage; primitive neuroectodermal tumor; Prosencephalon - metabolism; Prosencephalon - pathology; Proto-Oncogene Proteins c-sis - genetics; Proto-Oncogene Proteins c-sis - metabolism; Receptor, Notch1 - genetics; Receptor, Notch1 - metabolism; Receptor, Notch2 - genetics; Receptor, Notch2 - metabolism; Receptors, Notch - genetics; Receptors, Notch - metabolism; Recombinant Proteins - administration & dosage; Repressor Proteins - genetics; Repressor Proteins - metabolism; Signal Transduction; Time Factors; Tumor Burden; Tumor Suppressor Protein p53 - genetics; Tumor Suppressor Protein p53 - metabolism; Tumor Suppressor Proteins - genetics; Tumor Suppressor Proteins - metabolism; brain tumor; glioma; Notch signaling; Hes5; primitive neuroectodermal tumor
• ISSN: 1535-6108; 1878-3686
• DOI: 10.1016/j.ccell.2015.10.008

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.
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•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
Notch signaling has been implicated in promoting brain tumor development. Giachino et al. now show that inactivating Notch signaling accelerates the growth of Trp53−/−, PDGF-driven gliomas in mice and that high Notch pathway activity correlates with better survival of patients with some subtypes of glioma.