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Synthetic lethality through Gsk3β inhibition in glioma stem cells via the WNT-WWC1-YAP axis

Fangfang Ren1, Yulan Yi2, Ting Lu3

  • 1National Institute of Biological Sciences, Beijing, China.

Oncogene
|April 24, 2025
PubMed

Insights

Inhibiting Gsk3β activates the WNT pathway, reducing glioma stem cell growth and enhancing treatment sensitivity. This WNT-WWC1-YAP axis targeting offers a novel therapeutic strategy for aggressive brain tumors.

Area of Science:

  • Neuro-oncology
  • Molecular biology
  • Cancer stem cell research

Background:

  • Glioblastoma (GBM) is an aggressive brain tumor driven by glioma stem cells (GSCs).
  • GSCs contribute significantly to tumor growth and resistance to therapies.
  • Targeting GSCs is crucial for developing effective GBM treatments.

Purpose of the Study:

  • To investigate the effects of Gsk3β inhibition on GSC viability.
  • To elucidate the role of the canonical WNT signaling pathway in GSC response to Gsk3β inhibition.
  • To explore the potential of targeting the WNT-WWC1-YAP axis for glioma therapy.

Main Methods:

  • Gsk3β inhibition in GSCs.
  • Analysis of WNT pathway activation and downstream targets (Wwc1, Yap).
  • Assessment of GSC proliferation, self-renewal, and chemosensitivity.
  • Correlation analysis with clinical glioma datasets.

Main Results:

  • Gsk3β inhibition activates the WNT signaling pathway in GSCs.
  • Activated WNT pathway upregulates Wwc1, which downregulates Yap via Lats1 phosphorylation.
  • Reduced GSC proliferation and self-renewal were observed.
  • Enhanced chemosensitivity and correlation of WNT pathway activation with improved prognosis in proneural gliomas (especially IDH1-mutated) were found.

Conclusions:

  • Targeting the WNT-WWC1-YAP axis, via Gsk3β inhibition, reduces GSC viability and enhances chemosensitivity.
  • This approach may induce synthetic lethality in GSCs, offering a promising therapeutic strategy for gliomas.
  • Exploiting WNT-induced synthetic lethality represents a novel avenue for glioma treatment.

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