Sglt2-Cre drives tumors that reproduce the features of human tRCC not only in its aggressiveness, but also at multiple other levels, including histologically (tumor architecture, cytology, and stromal features), ultrastructurally (expansion of lysosomes and autophagosomes), immunohistochemically (downregulation of epithelial markers and preservation of Pax8), and functionally (activation of cell cycle, autophagy-lysosome, and mTORC1 pathways). Here, PAX8 is linked to renal cell carcinoma associated with Xp11.2 translocations/TFE3 gene fusions.