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

doi:10.1016/j.celrep.2019.07.071

Driving Neuronal Differentiation through Reversal of an ERK1/2-miR-124-SOX9 Axis Abrogates Glioblastoma Aggressiveness

Cell Rep. 2019 Aug 20;28(8):2064-2079.e11. doi: 10.1016/j.celrep.2019.07.071.

Authors

Hanna Sabelström¹, Rebecca Petri², Ksenya Shchors³, Rahul Jandial⁴, Christin Schmidt¹, Rohit Sacheva², Selma Masic¹, Edith Yuan¹, Trenten Fenster¹, Michael Martinez¹, Supna Saxena¹, Theodore P Nicolaides⁵, Shirin Ilkhanizadeh⁶, Mitchel S Berger⁷, Evan Y Snyder⁸, William A Weiss⁹, Johan Jakobsson², Anders I Persson¹⁰

Affiliations

¹ 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.
² Lab of Molecular Neurogenetics, Wallenberg Neuroscience Center and Lund Stem Cell Center, Lund University, Lund 221 84, Sweden.
³ ORD-Rinat, Pfizer, Inc., 230 East Grand Avenue, South San Francisco, CA 94080, USA.
⁴ Division of Neurosurgery, City of Hope, Duarte, CA 91010, USA.
⁵ 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.
⁶ 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.
⁷ 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.
⁸ 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.
⁹ 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.
¹⁰ 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. Electronic address: anders.persson@ucsf.edu.

PMID: 31433983
DOI: 10.1016/j.celrep.2019.07.071

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.

Keywords: brain; cancer; differentiation; glioblastoma; glioma; microRNA; neural stem cell; neurogenesis; neuron; tumor.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Astrocytoma / genetics
Astrocytoma / pathology
Benzamides / pharmacology
Brain Neoplasms / genetics
Brain Neoplasms / pathology*
Cell Differentiation* / drug effects
Cell Line, Tumor
Cell Survival / drug effects
Diphenylamine / analogs & derivatives
Diphenylamine / pharmacology
Disease Progression
Female
Glioblastoma / genetics
Glioblastoma / pathology*
Humans
MAP Kinase Signaling System* / drug effects
Male
Mice, Nude
MicroRNAs / genetics
MicroRNAs / metabolism*
Neoplasm Invasiveness
Neoplastic Stem Cells / drug effects
Neoplastic Stem Cells / metabolism
Neoplastic Stem Cells / pathology
Neurogenesis / drug effects
Neurons / drug effects
Neurons / metabolism
Neurons / pathology*
Phenotype
Protein Kinase Inhibitors / pharmacology
Radiation Tolerance / drug effects
SOX9 Transcription Factor / metabolism*

Substances

Benzamides
MIRN124 microRNA, human
MicroRNAs
Protein Kinase Inhibitors
SOX9 Transcription Factor
mirdametinib
Diphenylamine

Abstract

Publication types

MeSH terms

Substances

Grants and funding