Bap1 and Pbrm1: Determinants of Tumor Grade and mTOR Activation in VHL-Deficient Mouse Models of Renal Cell Carcinoma

Abstract

<b/> Large genome sequencing efforts have identified frequent mutations in the histone-modifying and chromatin-remodeling genes BAP1 and PBRM1 in clear cell renal cell carcinoma (ccRCC). In this issue of Cancer Discovery, Gu and colleagues model these genetic events in mice and report that dual inactivation of Vhl with either Bap1 or Pbrm1 results in faithful genetically engineered murine models of ccRCC. Moreover, their work establishes that Bap1 and Pbrm1 are determinants of tumor grade and mTORC1 activation and provocatively suggests that the cell of origin of ccRCC may lie in PAX8-expressing Bowman capsule cells. Cancer Discov; 7(8); 802-4. ©2017 AACRSee related article by Gu et al., p. 900.

Figure 1.

Cre-specific phenotypes and determinants of tumor grade in RCC mouse models. Six2, Pax8, Villin, and Sglt2 Cre strains all have unique expression patterns within the nephron. Inactivation of Vhl and Bap1 by either Six2-Cre or Pax8-Cre results in high-grade ccRCC with high levels of mTORC1 activation, whereas inactivation of Vhl and Pbrm1 by Pax8-Cre results in low-grade ccRCC with low levels of pS6. Pax8-Cre; Vhl^F/F; Pbrm1^F/F tumors can be transformed into high-grade tumors by additional heterozygous deletion of Tsc1 and resultant mTORC1 activation. Deletion of Vhl and Bap1 or Vhl and Pbrm1 using the proximal tubule–specific promoters Villin-Cre or Sglt2-Cre did not result in tumors, suggesting that the cell of origin of ccRCC in mice is a Pax8-expressing cell that lies outside of the proximal tubule.