tRCC mice modeling. Comparative Genomics of Novel Translocation Renal Cell Carcinoma Mouse Model Reveals Molecular Mechanisms of Tumorigenesis

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 nephrogenesis and glomerular 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 contexts, ASPSCR1-TFE3 led to characteristic morphological cellular changes, loss of epithelial markers, and an EMT program, but tumors only developed in the Sglt2 lineage. Electron microscopy of tRCC tumors showed lysosome expansion and functional studies revealed simultaneous activation of autophagy and mTORC1 pathways. Comparative genomic analyses with an institutional human tRCC cohort (including a previously unreported SFPQ-TFEB fusion and a variety of tumorgraft models [ASPSCR1-TFE3, PRCC-TFE3, SFPQ-TFE3, RBM10-TFE3 and MALAT1-TFEB]) disclosed significant convergence in canonical (cell cycle, lysosome and mTORC1) and less established pathways such as Myc, E2F and inflamation (IL6, TLR, interferon-γ and NK cell-mediated cytotoxicity). Therapeutic trials (adjusted for human drug exposures) showed anti-tumor activity of cabozantinib. Overall, this study provides insight into MiT/TFE-driven tumorigenesis, the cell of origin, and characterizes different mouse models available for research.