Comparative genomics incorporating translocation renal cell carcinoma mouse model reveals molecular mechanisms of tumorigenesis

J Clin Invest. 2024 Feb 22:e170559. doi: 10.1172/JCI170559. Online ahead of print.ABSTRACTTranslocation 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. However, in both contexts, ASPSCR1-TFE3 led to characteristic morphological cellular changes, loss of epithelial markers, and an EMT program. Electron microscopy of tRCC tumors showed lysosome expansion and functional studies revealed simultaneous activation of autophagy and mTORC1 pathways. Comparative genomic analyses encompassing an institutional human tRCC cohort (including a hitherto 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 inflammation (IL6/JAK/STAT3, interferon-γ, TLR signaling, systemic lupus, etc). Therapeutic trials (adjusted for human drug exposures) showed anti-tumor activity of cabozantinib. Overall, this study provides insight into MiT/TFE-driven tumorigenesis including the cell of origin and characterizes diverse...
Source: Genomics Proteomics ... - Category: Genetics & Stem Cells Authors: Source Type: research