An engineered tumor organoid model reveals cellular identity and signaling trajectories underlying SFPQ-TFE3 driven translocation RCC.

Translocation renal cell carcinoma (tRCC) is a rare, aggressive kidney cancer primarily occurring in children. They are genetically defined by translocations involving MiT/TFE gene family members or . The biology underlying tRCC development remains poorly understood, partly due to the lack of representative experimental models. We utilized human kidney organoids, or tubuloids, to engineer a tRCC model by expressing one of the most common MiT/TFE fusions, SFPQ-TFE3. Fusion-expressing tubuloids adopt a tRCC-like phenotype and gene expression signature and grow as clear cell RCC upon xenotransplantation in mice. Genome-wide binding analysis suggests that SFPQ-TFE3 reprograms gene expression signatures by widespread, aberrant DNA binding. Combining these analyses with single-cell mRNA readouts reveals a derailed epithelial differentiation trajectory that is at the root of transformation toward tRCC. Our study demonstrates that SFPQ-TFE3 expression is sufficient to transform kidney epithelial cells into tRCC and defines the trajectories underlying malignant transformation.