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

Hanna Sabelström1, Rebecca Petri2, Ksenya Shchors3

  • 1Department 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.

Cell Reports
|August 22, 2019
PubMed

Insights

Constitutive extracellular signal-regulated kinase 1/2 (ERK1/2) activation drives glioblastoma stemness and treatment resistance. Inhibiting ERK1/2 promotes neuronal differentiation, reducing tumor aggressiveness and increasing radiation sensitivity.

Area of Science:

  • Oncology
  • Neuroscience
  • Molecular Biology

Background:

  • Glioblastoma (GBM) is the most common primary malignant brain tumor.
  • Cancer stem-like properties contribute to treatment resistance and poor patient outcomes.
  • Identifying the molecular drivers of GBM stemness is crucial for developing effective therapies.

Purpose of the Study:

  • To investigate the role of extracellular signal-regulated kinase 1/2 (ERK1/2) activation in maintaining glioblastoma stemness.
  • To explore the therapeutic potential of targeting the ERK1/2 pathway for GBM treatment.

Main Methods:

  • Utilized murine astrocytoma models and human glioblastoma cell lines (GBM tumorspheres).
  • Employed pharmacological inhibition of ERK1/2 activation.
  • Analyzed miRNA expression profiles and gene targets (SOX9).
  • Assessed neurogenesis, neuronal differentiation, tumorigenicity, and radiation sensitivity.

Main Results:

  • Constitutive ERK1/2 activation sustains a stem-like state in GBM.
  • Inhibition of ERK1/2 restores neurogenesis and induces neuronal differentiation in GBM tumorspheres.
  • ERK1/2 regulates global miRNA expression in GBM.
  • Neuronal differentiation following ERK1/2 inhibition requires miR-124 and SOX9 depletion.
  • miR-124 overexpression promotes a stem-like-to-neuronal transition, reducing GBM tumorigenicity and increasing radiation sensitivity.

Conclusions:

  • Reversal of the ERK1/2-miR-124-SOX9 axis induces a neuronal phenotype in GBM.
  • Enforcing neuronal differentiation via this axis represents a promising therapeutic strategy for improving GBM patient outcomes.
Keywords:
braincancerdifferentiationglioblastomagliomamicroRNAneural stem cellneurogenesisneurontumor

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