Novel Model of tRCC
Translocation Renal Cell Carcinoma (tRCC) most commonly involves an ASPSCR1-TFE3 fusion, but molecular mechanisms remain elusive and animal models are lacking. Here, we show that human ASPSCR1-TFE3 driven by Pax8-Cre (a credentialed ccRCC driver) disrupted nephron development causing neonatal death, whilst the ccRCC failed driver, Sglt2-Cre, induced aggressive tRCC (as well as ASPS) with complete penetrance and short latency. In both models, ASPSCR1-TFE3 led to characteristic morphological cellular changes, loss of epithelial markers, and an EMT program, but only in the Sglt2 lineage was proliferation increased, revealing an uncoupling of cell fate and proliferation programs. Electron microscopy showed expansion of autolysosomes and functional studies revealed simultaneous activation of autophagy and mTORC1 pathways. Comparative genomic analyses with an institutional human tRCC cohort (including 6 tumorgraft models) disclosed significant convergence in canonical (cell cycle, lysosome and mTORC1) and less established pathways Amidst the heterogeneity of the tRCC mutational landscape, our cohort provides pertinent additions, and we observe a moderate degree of overlap between our human and murine cohorts and prior studies. Therapeutic trials adjusted for human drug exposures showed anti-tumor activity of cabozantinib. Overall, this study provides insight into MiT/TFE-driven tumorigenesis and the cell of origin and characterizes several models (GEMM and tumorgraft) for research.