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Here, we show that human\n                    <jats:italic>ASPSCR1-TFE3<\/jats:italic>\n                    driven by Pax8-Cre (a credentialed clear cell RCC driver) disrupted nephrogenesis and glomerular development, causing neonatal death, while the clear cell RCC failed driver, Sglt2-Cre, induced aggressive tRCC (as well as alveolar soft part sarcoma) with complete penetrance and short latency. However, in both contexts, ASPSCR1-TFE3 led to characteristic morphological cellular changes, loss of epithelial markers, and an epithelial-mesenchymal transition. 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\n                    <jats:italic>SFPQ-TFEB<\/jats:italic>\n                    fusion) and a variety of tumorgraft models (\n                    <jats:italic>ASPSCR1-TFE3<\/jats:italic>\n                    ,\n                    <jats:italic>PRCC-TFE3<\/jats:italic>\n                    ,\n                    <jats:italic>SFPQ-TFE3<\/jats:italic>\n                    ,\n                    <jats:italic>RBM10-TFE3<\/jats:italic>\n                    , and\n                    <jats:italic>MALAT1-TFEB<\/jats:italic>\n                    ) disclosed significant convergence in canonical pathways (cell cycle, lysosome, and mTORC1) and less established pathways such as Myc, E2F, and inflammation (IL-6\/JAK\/STAT3, interferon-\u03b3, TLR signaling, systemic lupus, etc.). Therapeutic trials (adjusted for human drug exposures) showed antitumor activity of cabozantinib. Overall, this study provides insight into MiT\/TFE-driven tumorigenesis, including the cell of origin, and characterizes diverse mouse models available for research.\n                  <\/jats:p>","DOI":"10.1172\/jci170559","type":"journal-article","created":{"date-parts":[[2024,2,22]],"date-time":"2024-02-22T12:00:35Z","timestamp":1708603235000},"source":"Crossref","is-referenced-by-count":31,"title":["Comparative genomics incorporating translocation renal cell carcinoma mouse model reveals molecular mechanisms of tumorigenesis"],"prefix":"10.1172","volume":"134","author":[{"given":"Gopinath","family":"Prakasam","sequence":"first","affiliation":[{"name":"Kidney Cancer Program, Simmons Comprehensive Cancer Center,"},{"name":"Hematology-Oncology Division, Department of Internal 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