Deletion of Lats1/2 in adult kidney epithelia leads to renal cell carcinoma

Phoebe Carter; Ulrike Schnell; Christopher Chaney; Betty Tong; Xinchao Pan; Jianhua Ye; Glenda Mernaugh; Jennifer L Cotton; Vitaly Margulis; Junhao Mao; Roy Zent; Bret M Evers; Payal Kapur; Thomas J Carroll

doi:10.1172/JCI144108

Deletion of Lats1/2 in adult kidney epithelia leads to renal cell carcinoma

J Clin Invest. 2021 Jun 1;131(11):e144108. doi: 10.1172/JCI144108.

Authors

Phoebe Carter¹, Ulrike Schnell¹, Christopher Chaney¹, Betty Tong¹, Xinchao Pan¹, Jianhua Ye¹, Glenda Mernaugh², Jennifer L Cotton³, Vitaly Margulis⁴, Junhao Mao³, Roy Zent², Bret M Evers^{5

6}, Payal Kapur^{4

5}, Thomas J Carroll¹

Affiliations

¹ Department of Molecular Biology and Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
² Department of Medicine, Division of Nephrology, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
³ Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
⁴ Department of Urology.
⁵ Department of Pathology, and.
⁶ Department of Ophthalmology, University of Texas Southwestern Medical Center, Dallas, Texas, USA.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.

Abstract

Keywords: Cancer; Cell Biology; Mouse models; Oncology; Tumor suppressors.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Animals
Carcinoma, Renal Cell* / enzymology
Carcinoma, Renal Cell* / genetics
Carcinoma, Renal Cell* / pathology
Gene Deletion*
Humans
Kidney / metabolism*
Kidney / pathology
Kidney Neoplasms* / enzymology
Kidney Neoplasms* / genetics
Kidney Neoplasms* / pathology
Mice
Mice, Transgenic
Protein Serine-Threonine Kinases* / deficiency
Protein Serine-Threonine Kinases* / metabolism
Tumor Suppressor Proteins* / deficiency
Tumor Suppressor Proteins* / metabolism

Substances

Tumor Suppressor Proteins
Lats1 protein, mouse
LATS2 protein, mouse
Protein Serine-Threonine Kinases

Abstract

Publication types

MeSH terms

Substances

Grants and funding