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

Research output: Contribution to journalArticle

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. 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.

Details

Authors
  • H. Sabelström
  • Rebecca Petri
  • Ksenya Shchors
  • R. Jandial
  • Christin Schmidt
  • Rohit Sacheva
  • S. Masic
  • E. Yuan
  • Trenten Fenster
  • Michael Martinez
  • S. Saxena
  • Theodore P. Nicolaides
  • Shirin Ilkhanizadeh
  • Mitchel S. Berger
  • Evan Y. Snyder
  • William A. Weiss
  • J. Jakobsson
  • Anders I. Persson
Organisations
External organisations
  • Pfizer Inc. US
  • City of Hope National Medical Center
  • University of California, San Diego
  • University of California System
  • Lund University
  • University of Texas Health Science Centre
  • UCSF Helen Diller Family Comprehensive Cancer Center
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Cell and Molecular Biology

Keywords

  • brain, cancer, differentiation, glioblastoma, glioma, microRNA, neural stem cell, neurogenesis, neuron, tumor
Original languageEnglish
Pages (from-to)2064-2079.e11
JournalCell Reports
Volume28
Issue number8
Publication statusPublished - 2019
Publication categoryResearch
Peer-reviewedYes