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Driving Neuronal Differentiation through Reversal of an ERK1/2-miR-124-SOX9 Axis Abrogates Glioblastoma Aggressiveness.
Sabelström, Hanna; Petri, Rebecca; Shchors, Ksenya; Jandial, Rahul; Schmidt, Christin; Sacheva, Rohit; Masic, Selma; Yuan, Edith; Fenster, Trenten; Martinez, Michael; Saxena, Supna; Nicolaides, Theodore P; Ilkhanizadeh, Shirin; Berger, Mitchel S; Snyder, Evan Y; Weiss, William A; Jakobsson, Johan; Persson, Anders I.
Affiliation
  • Sabelström H; Department of Neurology, University of California, San Francisco, San Francisco, CA 94158, USA; Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA 94158, USA; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Fran
  • Petri R; Lab of Molecular Neurogenetics, Wallenberg Neuroscience Center and Lund Stem Cell Center, Lund University, Lund 221 84, Sweden.
  • Shchors K; ORD-Rinat, Pfizer, Inc., 230 East Grand Avenue, South San Francisco, CA 94080, USA.
  • Jandial R; Division of Neurosurgery, City of Hope, Duarte, CA 91010, USA.
  • Schmidt C; Department of Neurology, University of California, San Francisco, San Francisco, CA 94158, USA; Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA 94158, USA; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Fran
  • Sacheva R; Lab of Molecular Neurogenetics, Wallenberg Neuroscience Center and Lund Stem Cell Center, Lund University, Lund 221 84, Sweden.
  • Masic S; Department of Neurology, University of California, San Francisco, San Francisco, CA 94158, USA; Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA 94158, USA; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Fran
  • Yuan E; Department of Neurology, University of California, San Francisco, San Francisco, CA 94158, USA; Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA 94158, USA; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Fran
  • Fenster T; Department of Neurology, University of California, San Francisco, San Francisco, CA 94158, USA; Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA 94158, USA; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Fran
  • Martinez M; Department of Neurology, University of California, San Francisco, San Francisco, CA 94158, USA; Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA 94158, USA; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Fran
  • Saxena S; Department of Neurology, University of California, San Francisco, San Francisco, CA 94158, USA; Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA 94158, USA; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Fran
  • Nicolaides TP; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94158, USA; Department of Pediatrics, University of California, San Francisco, San Francisco, CA 94158, USA.
  • Ilkhanizadeh S; Department of Neurology, University of California, San Francisco, San Francisco, CA 94158, USA; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94158, USA.
  • Berger MS; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94158, USA; Department of Neurological Surgery and Brain Tumor Research Center, University of California, San Francisco, San Francisco, CA 94158, USA.
  • Snyder EY; Center for Stem Cells and Regenerative Medicine, Sanford Burnham Prebys Medical Discovery Institute, and Department of Pediatrics, University of California, San Diego, San Diego, CA 92037, USA.
  • Weiss WA; Department of Neurology, University of California, San Francisco, San Francisco, CA 94158, USA; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94158, USA; Department of Neurological Surgery and Brain Tumor Research Center, University of Ca
  • Jakobsson J; Lab of Molecular Neurogenetics, Wallenberg Neuroscience Center and Lund Stem Cell Center, Lund University, Lund 221 84, Sweden.
  • Persson AI; Department of Neurology, University of California, San Francisco, San Francisco, CA 94158, USA; Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA 94158, USA; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Fran
Cell Rep ; 28(8): 2064-2079.e11, 2019 08 20.
Article in En | MEDLINE | ID: mdl-31433983
ABSTRACT
Identifying cellular programs that drive cancers to be stem-like and treatment resistant is critical to improving outcomes in patients. Here, we demonstrate that constitutive extracellular signal-regulated kinase 1/2 (ERK1/2) activation sustains a stem-like state in glioblastoma (GBM), the most common primary malignant brain tumor. Pharmacological inhibition of ERK1/2 activation restores neurogenesis during murine astrocytoma formation, inducing neuronal differentiation in tumorspheres. Constitutive ERK1/2 activation globally regulates miRNA expression in murine and human GBMs, while neuronal differentiation of GBM tumorspheres following the inhibition of ERK1/2 activation requires the functional expression of miR-124 and the depletion of its target gene SOX9. Overexpression of miR124 depletes SOX9 in vivo and promotes a stem-like-to-neuronal transition, with reduced tumorigenicity and increased radiation sensitivity. Providing a rationale for reports demonstrating miR-124-induced abrogation of GBM aggressiveness, we conclude that reversal of an ERK1/2-miR-124-SOX9 axis induces a neuronal phenotype and that enforcing neuronal differentiation represents a therapeutic strategy to improve outcomes in GBM.
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Brain Neoplasms / Cell Differentiation / Glioblastoma / MAP Kinase Signaling System / MicroRNAs / SOX9 Transcription Factor / Neurons Type of study: Prognostic_studies Limits: Animals / Female / Humans / Male Language: En Journal: Cell Rep Year: 2019 Document type: Article
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Brain Neoplasms / Cell Differentiation / Glioblastoma / MAP Kinase Signaling System / MicroRNAs / SOX9 Transcription Factor / Neurons Type of study: Prognostic_studies Limits: Animals / Female / Humans / Male Language: En Journal: Cell Rep Year: 2019 Document type: Article