Driving Neuronal Differentiation through Reversal of an ERK1/2-miR-124-SOX9 Axis Abrogates Glioblastoma Aggressiveness
Hanna Sabelström,
Rebecca Petri,
Ksenya Shchors,
Rahul Jandial,
Christin Schmidt,
Rohit Sacheva,
Selma Masic,
Edith Yuan,
Trenten Fenster,
Michael Martinez,
Supna Saxena,
Theodore P. Nicolaides,
Shirin Ilkhanizadeh,
Mitchel S. Berger,
Evan Y. Snyder,
William A. Weiss,
Johan Jakobsson,
Anders I. Persson
Affiliations
Hanna Sabelström
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 Francisco, CA 94158, USA
Rebecca Petri
Lab of Molecular Neurogenetics, Wallenberg Neuroscience Center and Lund Stem Cell Center, Lund University, Lund 221 84, Sweden
Ksenya Shchors
ORD-Rinat, Pfizer, Inc., 230 East Grand Avenue, South San Francisco, CA 94080, USA
Rahul Jandial
Division of Neurosurgery, City of Hope, Duarte, CA 91010, USA
Christin Schmidt
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 Francisco, CA 94158, USA
Rohit Sacheva
Lab of Molecular Neurogenetics, Wallenberg Neuroscience Center and Lund Stem Cell Center, Lund University, Lund 221 84, Sweden
Selma Masic
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 Francisco, CA 94158, USA
Edith Yuan
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 Francisco, CA 94158, USA
Trenten Fenster
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 Francisco, CA 94158, USA
Michael Martinez
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 Francisco, CA 94158, USA
Supna Saxena
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 Francisco, CA 94158, USA
Theodore P. Nicolaides
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
Shirin Ilkhanizadeh
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
Mitchel S. Berger
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
Evan Y. Snyder
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
William A. Weiss
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 California, San Francisco, San Francisco, CA 94158, USA; Department of Pediatrics, University of California, San Francisco, San Francisco, CA 94158, USA
Johan Jakobsson
Lab of Molecular Neurogenetics, Wallenberg Neuroscience Center and Lund Stem Cell Center, Lund University, Lund 221 84, Sweden
Anders I. Persson
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 Francisco, CA 94158, USA; Department of Neurological Surgery and Brain Tumor Research Center, University of California, San Francisco, San Francisco, CA 94158, USA; Corresponding author
Summary: 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. : Sabelström et al. show that the loss of neurogenesis is reversible during neural stem cell-derived glioma formation. Pharmacological inhibition of ERK1/2 globally regulates miRNAs and induces neuronal differentiation, a process that is dependent on the modulation of an miR-124-SOX9 axis in glioblastoma (GBM) cells. The overexpression of miR-124 induces neuronal differentiation that abrogates GBM aggressiveness. Keywords: brain, cancer, differentiation, glioma, glioblastoma, microRNA, neural stem cell, neurogenesis, neuron, tumor
