Renal cell carcinoma (RCC) is the most common kidney cancer in humans. Misregulation of the Hippo/Warts pathway is frequently reported in RCC, suggesting a role in disease formation/progression. Paradoxically, misregulation of this pathway is also observed in non-tumorigenic kidney diseases, raising questions as to its specific role in RCC. Here, we show that ablation of the Warts kinases Lats1 and Lats2 in mature renal epithelia was sufficient to cause metastatic RCC in mice. Distinct tumors with sarcomatoid histology were present in mutant kidneys 3 months after genetic ablation. Tumor formation required the downstream effectors Yap and Taz, and treatment with verteporfin, a drug that inhibits Yap activity, could slow progression of the disease. Examination of human tissues showed that among histological subtypes of RCC, nuclear YAP was most commonly observed in sarcomatoid RCC. However, analysis of transcriptomic data from human RCC revealed a unique subset with a molecular signature that closely resembled the transcriptome of Lats mutants. Together, these findings show that misregulation of the Warts pathway is sufficient to drive renal tumor formation in mice and suggest that human tumors with active YAP may represent a unique subset of RCCs that can be therapeutically targeted.
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