• First comprehensive Hippo-VHL nexus analysis in ccRCC tumorigenesis. • 3p loss creates unique 'double hit' disrupting VHL and RASSF1 pathways. • LATS1/2 convergence creates self-reinforcing HIF-Hippo oncogenic loop. • Hippo components serve as prognostic biomarkers for patient stratification. • Complements VHL-centric view, positions Hippo as emerging therapeutic target. Clear cell renal cell carcinoma (ccRCC) represents 70% of kidney cancers, with 20–50% recurrence risk after surgery. Despite therapeutic advances, no reliable biomarkers have been identified for patient stratification or treatment response prediction. While VHL gene alterations are well-established in ccRCC pathogenesis, the role of the Hippo pathway remains underexplored despite ample evidence of its involvement. This review synthesizes current knowledge on Hippo pathway alterations in ccRCC and examines its crosstalk with the VHL/HIF axis, identifying potential biomarkers and therapeutic targets. We comprehensively analyzed literature on Hippo pathway components in ccRCC, focusing on molecular mechanisms, clinical correlations, and interactions with VHL signaling. Multiple Hippo pathway alterations characterize ccRCC: RASSF1A hypermethylation, NF2 mutations (particularly in aggressive variants), SAV1 downregulation associated with 14q loss, and LATS1/2 methylation-mediated inactivation. These changes result in YAP/TAZ nuclear accumulation and oncogenic transcription. Importantly, chromosome 3p loss simultaneously disrupts both VHL and RASSF1, creating a unique double-hit scenario. The VHL-Hippo crosstalk operates through multiple mechanisms: HIF-induced GPRC5A and VEGFR signaling inhibit LATS1/2 phosphorylation, promoting YAP/TAZ activation, while active YAP/TAZ enhances pro-angiogenic gene transcription, amplifying hypoxic responses. Low expression of RASSF1A, SAV1, and LATS1/2, coupled with high YAP/TAZ activity, correlates with advanced tumor stage, higher grade, and poorer survival. The Hippo pathway represents a critical yet underappreciated dimension of ccRCC biology, offering promising biomarkers for risk stratification and novel therapeutic targets. The Hippo-VHL nexus presents multiple intervention points that could enhance current treatment.
Waeckel et al. (Sat,) studied this question.