@article{e4d371df7cb34f04a4d8c68ef1e52ddc,
title = "Deletion of Lats1/2 in adult kidney epithelia leads to renal cell carcinoma",
abstract = "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.",
author = "Phoebe Carter and Ulrike Schnell and Christopher Chaney and Betty Tong and Xinchao Pan and Jianhua Ye and Glenda Mernaugh and Cotton, {Jennifer L.} and Vitaly Margulis and Junhao Mao and Roy Zent and Evers, {Bret M.} and Payal Kapur and Carroll, {Thomas J.}",
note = "Funding Information: versity of Texas MD Anderson Cancer Center for providing RosaYap5SA mice. This work was supported by grants from the Cancer Prevention and Research Institute of Texas (RP160340) and the NIH (R24DK106743, R01DK095057, P50CA196516) to TJC, from the NIH (P50CA196516) to PK, and from the NIH (R01DK069921) and the Department of Veterans Affairs, Veterans Health Administration, Office of Research and Develop- ment (1I01BX002196) to RZ. The graphical abstract was created with BioRender (Biorender.com). Funding Information: We thank Ondine Cleaver, Denise Marciano, and James Brugarolas and members of the UTSW Kidney Cancer Center and the Carroll, Cleaver, and Marciano laboratories for comments. We thank Eric Olson of the University of Texas Southwestern Medical Center for providing Yapfl/fl and Tazfl/fl mice, and Randy L. Johnson of The University of Texas MD Anderson Cancer Center for providing RosaYap5SA mice. This work was supported by grants from the Cancer Prevention and Research Institute of Texas (RP160340) and the NIH (R24DK106743, R01DK095057, P50CA196516) to TJC, from the NIH (P50CA196516) to PK, and from the NIH (R01DK069921) and the Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development (1I01BX002196) to RZ. The graphical abstract was created with BioRender (Biorender.com). Publisher Copyright: {\textcopyright} 2021, American Society for Clinical Investigation.",
year = "2021",
month = jun,
doi = "10.1172/JCI144108",
language = "English (US)",
volume = "131",
journal = "Journal of Clinical Investigation",
issn = "0021-9738",
publisher = "The American Society for Clinical Investigation",
number = "11",
}