FoxOs Enforce a Progression Checkpoint to Constrain mTORC1-Activated Renal Tumorigenesis

Abstract

mTORC1 is a validated therapeutic target for renal cell carcinoma (RCC). Here, analysis of Tsc1 deficient (mTORC1 hyperactivation) mice uncovered a FoxO-dependent negative feedback circuit constraining mTORC1-mediated renal tumorigenesis. We document robust FoxO activation in Tsc1 deficient benign polycystic kidneys and FoxO extinction upon progression to murine renal tumors; murine renal tumor progression upon genetic deletion of both Tsc1 and FoxOs; and down-regulated FoxO expression in most human renal clea…