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

Clear cell renal cell carcinoma (ccRCC) is characterized by BAP1 and PBRM1 mutation, which are associated with tumors of different grade and prognosis. However, whether BAP1 and PBRM1 loss causes ccRCC and determines tumor grade is unclear. We conditionally targeted Bap1 and Pbrm1 (with Vhl) in the mouse using several Cre drivers. Sglt2 and Villin proximal convoluted tubule drivers failed to cause tumorigenesis, challenging the conventional notion of ccRCC origins. In contrast, targeting with Pax8, a developmental lineage-specific transcription factor, led to ccRCC of different grade. Bap1-deficient tumors were high grade and showed greater mTORC1 activation than Pbrm1-deficient tumors, which exhibited longer latency. Disrupting one allele of the mTORC1 negative regulator, Tsc1, in Pbrm1-deficient kidneys triggered higher grade ccRCC. This study establishes Bap1 and Pbrm1 as lineage-specific drivers of ccRCC and histological grade, implicates mTORC1 as a tumor grade rheostat, and suggests that ccRCC may arise from Bowman capsule cells.

Cancer discovery. 2017 May 04 [Epub ahead of print]

Yi-Feng Gu, Shannon Cohn, Alana Christie, Tiffani McKenzie, Nicholas C Wolff, Quyen N Do, Ananth Madhuranthakam, Ivan Pedrosa, Tao Wang, Anwesha Dey, Meinrad Busslinger, Xian-Jin Xie, Robert E Hammer, Renée M McKay, Payal Kapur, James Brugarolas

Department of Internal Medicine, Hematology-Oncology Division, University of Texas Southwestern Medical Center., Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center., University of Texas Southwestern Medical Center., Radiology, University of Texas Southwestern Medical Center., Department of Clinical Sciences, University of Texas Southwestern Medical Center., Department of Molecular Oncology, Genentech., Department of Immunology, Research Institute of Molecular Pathology., Simmons Comprehensive Cancer Center, University of Texas at Southwestern Medical Center., Biochemistry, University of Texas Southwestern Medical Center., Internal Medicine - Hematology-Oncology Division, University of Texas Southwestern Medical Center .