title: A Tumor Suppressor Function for Notch Signaling in Forebrain Tumor Subtypes.
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.
authors.affiliation: Department of Biomedicine, University of Basel, Mattenstrasse 28, 4058 Basel, Switzerland. Electronic address: claudio.giachino@unibas.ch.
authors.forename: Claudio
authors.initials: C
authors.lastname: Giachino
authors.affiliation: Department of Biomedicine, University Hospital Basel, Spitalstrasse 21, 4031 Basel, Switzerland.
authors.forename: Jean-Louis
authors.initials: JL
authors.lastname: Boulay
authors.affiliation: Department of Biomedicine, University of Basel, Mattenstrasse 28, 4058 Basel, Switzerland.
authors.forename: Robert
authors.initials: R
authors.lastname: Ivanek
authors.affiliation: Department of Cellular and Molecular Medicine, Lerner Research Institute, Cleveland Clinic, 9500 Euclid Avenue, NC 10, Cleveland, OH 44195, USA.
authors.forename: Alvaro
authors.initials: A
authors.lastname: Alvarado
authors.affiliation: Department of Biomedicine, University Hospital Basel, Spitalstrasse 21, 4031 Basel, Switzerland.
authors.forename: Cristobal
authors.initials: C
authors.lastname: Tostado
authors.affiliation: Department of Biomedicine, University of Basel, Mattenstrasse 28, 4058 Basel, Switzerland.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Lugert
authors.affiliation: Department of Biomedicine, University of Basel, Kingelbergstrasse 50-70, 4056 Basel, Switzerland.
authors.forename: Jan
authors.initials: J
authors.lastname: Tchorz
authors.affiliation: Department of Biomedicine, University of Basel, Mattenstrasse 28, 4058 Basel, Switzerland.
authors.forename: Mustafa
authors.initials: M
authors.lastname: Coban
authors.affiliation: Department of Biomedicine, University Hospital Basel, Spitalstrasse 21, 4031 Basel, Switzerland.
authors.forename: Luigi
authors.initials: L
authors.lastname: Mariani
authors.affiliation: Department of Biomedicine, University of Basel, Kingelbergstrasse 50-70, 4056 Basel, Switzerland.
authors.forename: Bernhard
authors.initials: B
authors.lastname: Bettler
authors.affiliation: Department of Cellular and Molecular Medicine, Lerner Research Institute, Cleveland Clinic, 9500 Euclid Avenue, NC 10, Cleveland, OH 44195, USA.
authors.forename: Justin
authors.initials: J
authors.lastname: Lathia
authors.affiliation: Division of Neuropathology, Institute of Pathology, University of Basel, Schoenbeinstrasse 40, 4031 Basel, Switzerland.
authors.forename: Stephan
authors.initials: S
authors.lastname: Frank
authors.affiliation: Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), 69121 Heidelberg, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Pfister
authors.affiliation: Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), 69121 Heidelberg, Germany.
authors.forename: Marcel
authors.initials: M
authors.lastname: Kool
authors.affiliation: Department of Biomedicine, University of Basel, Mattenstrasse 28, 4058 Basel, Switzerland. Electronic address: verdon.taylor@unibas.ch.
authors.forename: Verdon
authors.initials: V
authors.lastname: Taylor
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism; D001932:Brain Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D049109:Cell Proliferation; D030541:Databases, Genetic; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D018014:Gene Transfer Techniques; D005910:Glioma / Q000235:genetics / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D006801:Humans; D051819:Immunoglobulin J Recombination Signal Sequence-Binding Protein / Q000235:genetics / Q000378:metabolism; D057967:Infusions, Intraventricular; D053208:Kaplan-Meier Estimate; D018345:Mice, Knockout; D060787:Neoplasm Grading; D014411:Neoplastic Stem Cells / Q000378:metabolism* / Q000473:pathology; D058953:Neural Stem Cells / Q000378:metabolism* / Q000473:pathology; D010641:Phenotype; D010982:Platelet-Derived Growth Factor / Q000008:administration & dosage; D016548:Prosencephalon / Q000378:metabolism* / Q000473:pathology; D020574:Proto-Oncogene Proteins c-sis / Q000235:genetics / Q000378:metabolism; D051881:Receptor, Notch1 / Q000235:genetics / Q000378:metabolism; D051883:Receptor, Notch2 / Q000235:genetics / Q000378:metabolism; D051880:Receptors, Notch / Q000235:genetics / Q000378:metabolism*; D011994:Recombinant Proteins / Q000008:administration & dosage; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D013997:Time Factors; D047368:Tumor Burden; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D051819:Immunoglobulin J Recombination Signal Sequence-Binding Protein; D010982:Platelet-Derived Growth Factor; D020574:Proto-Oncogene Proteins c-sis; D051881:Receptor, Notch1; D051883:Receptor, Notch2; D051880:Receptors, Notch; D011994:Recombinant Proteins; D012097:Repressor Proteins; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; C489685:Hes5 protein, mouse; C497762:Notch1 protein, mouse; C497765:Notch2 protein, mouse; C497571:Rbpj protein, mouse; C075278:platelet-derived growth factor A
keywords: Hes5; Notch signaling; brain tumor; glioma; primitive neuroectodermal tumor