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Monitoring Hippo Signaling Pathway Activity Using a Luciferase-based Large Tumor Suppressor LATS Biosensor
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Monitoring Hippo Signaling Pathway Activity Using a Luciferase-based Large Tumor Suppressor LATS Biosensor

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ETV5 links the FGFR3 and Hippo signalling pathways in bladder cancer

Erica di Martino1, Olivia Alder1, Carolyn D Hurst1

  • 1University of Leeds, Leeds Institute of Medical Research at St James's, St. James's University Hospital, Leeds, LS9 7TF, UK.

Scientific Reports
|April 7, 2019
PubMed

Insights

Activating fibroblast growth factor receptor 3 (FGFR3) mutations drive bladder cancer by increasing ETV5 and TAZ levels, promoting uncontrolled cell growth. Inhibiting this pathway may offer a new therapeutic strategy for FGFR3-dependent urothelial carcinoma.

Area of Science:

  • Molecular Oncology
  • Urothelial Carcinogenesis
  • Signal Transduction

Background:

  • Activating mutations in fibroblast growth factor receptor 3 (FGFR3) are prevalent in urothelial carcinoma (UC) of the bladder.
  • FGFR3 mutations are recognized as key drivers of UC, and their inhibition reduces cancer cell malignancy.
  • The precise mechanisms by which FGFR3 activation promotes urothelial malignant transformation are not fully understood.

Purpose of the Study:

  • To investigate the role of the ETS-family transcription factor ETV5 as a downstream effector of FGFR3 signaling in bladder cancer.
  • To elucidate the molecular pathway linking FGFR3 activation to altered cell adhesion and proliferation in urothelial cells.
  • To identify potential therapeutic targets in FGFR3-driven urothelial tumors.

Main Methods:

  • Analysis of ETV5 and TAZ protein levels in response to FGFR3 signaling.
  • Investigated the involvement of the MAPK/ERK pathway in regulating ETV5 expression.
  • Utilized knockdown experiments of ETV5 in FGFR3-mutant bladder cancer cell lines to assess its role in proliferation and anchorage-independent growth.

Main Results:

  • FGFR3 signaling was shown to induce a MAPK/ERK-dependent increase in ETV5 levels.
  • Elevated ETV5 levels led to increased expression of TAZ, a regulator of cell-contact inhibition.
  • Knockdown of ETV5 significantly reduced proliferation and anchorage-independent growth in FGFR3-mutant bladder cancer cells, confirming its role as a mediator of oncogenic effects.

Conclusions:

  • ETV5 acts as a crucial downstream mediator of oncogenic FGFR3 signaling in urothelial carcinoma.
  • The FGFR3-ETV5-TAZ axis contributes to the loss of contact inhibition and promotes malignant transformation.
  • TAZ emerges as a potential therapeutic target for bladder tumors driven by FGFR3 mutations.

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