Vhl-/-Tsc1-/- mice rapidly develop clear cell renal cell carcinoma with pronounced metabolic and redox reprogramming that necessitates NRF2 signaling

Cancer genomics implicated that combined genetic losses of VHL and TSC1 are sufficient to initiate clear cell renal cell carcinoma (ccRCC) in human. Here, we engineered a mouse model with kidney-specific deletion of Vhl and Tsc1 . Vhl -/- Tsc1 -/- mice developed multifocal renal cell carcinoma starting at 7 weeks of age with 100% penetrance. These Vhl -/- Tsc1 -/- mouse kidney tumors mimicked the histopathology of human VHL -/- TSC1 -/- kidney tumors. Integrated transcriptomic and metabolomic analyses of 4-week-old precancerous mouse kidney cortex demonstrated that Vhl -/- Tsc1 -/- kidney cells not only exhibit heightened HIF and mTORC1 signals but also engage antioxidant response regulated by the Nuclear factor erythroid 2-related factor 2 (NFE2L2 or NRF2). Biochemical, cell biological, cancer multi-omic, and xenograft studies discovered NRF2-dependence in human VHL -/- TSC1 -/- ccRCC cells. Altogether, we report a mouse model recapitulating human VHL -/- TSC1 -/- ccRCC, delineate metabolic/redox reprogramming upon unbridled HIF and mTORC1 activation in the kidney cortex, and present unique therapeutic opportunities.