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Updated: Mar 3, 2026

Comparing Metastatic Clear Cell Renal Cell Carcinoma Model Established in Mouse Kidney and on Chicken Chorioallantoic Membrane
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The Hippo pathway in clear cell renal cell carcinoma (ccRCC): a nexus with the VHL disruption?

T Waeckel1, R Lefranc1, M Waeckel2

  • 1Université de Caen Normandie, CNRS, Normandie Univ, ISTCT UMR6030, CYCERON, F-14000 Caen, France; Centre Hospitalier Universitaire de Caen Normandie, Service d'Urologie et Transplantation, 14000 CAEN, France.

Translational Oncology
|March 1, 2026
PubMed
Abstract

Insights

The Hippo pathway is altered in clear cell renal cell carcinoma (ccRCC), impacting tumor progression and survival. Targeting the Hippo-VHL axis offers new biomarkers and therapies for ccRCC patients.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Clear cell renal cell carcinoma (ccRCC) has a high recurrence rate, lacking reliable biomarkers for patient stratification.
  • While VHL gene alterations are known drivers, the Hippo pathway's role in ccRCC is underexplored.

Purpose of the Study:

  • To review Hippo pathway alterations in ccRCC.
  • To examine Hippo pathway crosstalk with the VHL/HIF axis.
  • To identify potential ccRCC biomarkers and therapeutic targets.

Main Methods:

  • Comprehensive literature analysis of Hippo pathway components in ccRCC.
  • Focus on molecular mechanisms, clinical correlations, and VHL signaling interactions.

Main Results:

  • Hippo pathway alterations (RASSF1A hypermethylation, NF2 mutations, SAV1 downregulation, LATS1/2 inactivation) lead to YAP/TAZ activation in ccRCC.
  • Simultaneous 3p loss affects both VHL and RASSF1, creating a double-hit scenario.
  • VHL-Hippo crosstalk involves HIF-induced signaling inhibiting LATS1/2 and YAP/TAZ promoting angiogenesis; low RASSF1A/SAV1/LATS1/2 and high YAP/TAZ correlate with poor prognosis.

Conclusions:

  • The Hippo pathway is a critical, underappreciated factor in ccRCC biology.
  • Hippo pathway alterations offer promising biomarkers for ccRCC risk stratification.
  • The Hippo-VHL nexus provides novel therapeutic intervention points for ccRCC.
Keywords:
BiomarkerClear cell renal cell carcinomaEmerging therapeutic strategyHippo pathwayVHL

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