Modeling Renal Cell Carcinoma in Mice: Bap1 and Pbrm1 Inactivation Drive Tumor Grade

Clear cell renal cell carcinoma (ccRCC) is characterized by and mutations, which are associated with tumors of different grade and prognosis. However, whether and loss causes ccRCC and determines tumor grade is unclear. We conditionally targeted and (with ) in the mouse using several Cre drivers. an...

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Bibliographic Details
Published in:Cancer discovery 2017-08, Vol.7 (8), p.900-917
Main Authors: Gu, Yi-Feng, Cohn, Shannon, Christie, Alana, McKenzie, Tiffani, Wolff, Nicholas, Do, Quyen N, Madhuranthakam, Ananth J, Pedrosa, Ivan, Wang, Tao, Dey, Anwesha, Busslinger, Meinrad, Xie, Xian-Jin, Hammer, Robert E, McKay, Renée M, Kapur, Payal, Brugarolas, James
Format: Article
Language:English
Subjects:
Animals
Carcinogenesis - genetics
Carcinoma, Renal Cell - genetics
Carcinoma, Renal Cell - pathology
Disease Models, Animal
Gene Expression Regulation, Neoplastic
Genetic Predisposition to Disease - genetics
HMGB Proteins - genetics
Humans
Mice
Microfilament Proteins - genetics
Mutation
Prognosis
Sodium-Glucose Transporter 2 - genetics
Tumor Suppressor Proteins - genetics
Ubiquitin Thiolesterase - genetics
Von Hippel-Lindau Tumor Suppressor Protein - genetics
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Summary:Clear cell renal cell carcinoma (ccRCC) is characterized by and mutations, which are associated with tumors of different grade and prognosis. However, whether and loss causes ccRCC and determines tumor grade is unclear. We conditionally targeted and (with ) in the mouse using several Cre drivers. and proximal convoluted tubule drivers failed to cause tumorigenesis, challenging the conventional notion of ccRCC origins. In contrast, targeting with PAX8, a transcription factor frequently overexpressed in ccRCC, led to ccRCC of different grades. -deficient tumors were of high grade and showed greater mTORC1 activation than -deficient tumors, which exhibited longer latency. Disrupting one allele of the mTORC1 negative regulator, , in -deficient kidneys triggered higher grade ccRCC. This study establishes and as lineage-specific drivers of ccRCC and histologic grade, implicates mTORC1 as a tumor grade rheostat, and suggests that ccRCCs arise from Bowman capsule cells. Determinants of tumor grade and aggressiveness across cancer types are poorly understood. Using ccRCC as a model, we show that and loss drives tumor grade. Furthermore, we show that the conversion from low grade to high grade can be promoted by activation of mTORC1. .
ISSN:2159-8274
2159-8290
DOI:10.1158/2159-8290.cd-17-0292