SFPQ-TFE3 reciprocally regulates mTORC1 and induces lineage plasticity in a mouse model of renal tumorigenesis
- Kaushal Asrani
- Adrianna Amaral
- Juhyung Woo
- Sanaz Nourmohammadi Abadchi
- Thiago Vidotto
- Eddie Imada
- Alyza Skaist
- Kewen Feng
- Hans B. Liu
- Mithila Kasbe
- Yorifumi Satou
- Masaya Baba
- Yuichi Oike
- Patricia Outeda
- Terry Watnick
- Avi Z. Rosenberg
- Laura S. Schmidt
- W. Marston Linehan
- Pedram Argani
- Tamara L. Lotan
2025-10-03
MiT/TFE gene fusions like SFPQ-TFE3 drive both epithelial (translocation RCC) and mesenchymal (PEComas) neoplasms. However, no mouse models for SFPQ-TFE3 -related tumors exist and the underlying mechanisms of lineage plasticity remain unclear. Here, we demonstrate that constitutive murine renal expression of SFPQ-TFE3 disrupts kidney development with early neonatal renal failure and death, while post-natal induction induces infiltrative epithelioid tumors, that morphologically and transcriptionally resemble human PEComas, with strong activation of mTORC1 signaling via increased V-ATPase expression. Remarkably, SFPQ-TFE3 expression is sufficient to induce lineage plasticity, with down-regulation of the PAX2/PAX8 nephric lineage factors and tubular epithelial markers, and up-regulation of PEComa differentiation markers in transgenic mice, cell lines and human tRCC. mTOR inhibition downregulates SFPQ-TFE3 expression and rescues PAX8 expression and transcriptional activity in vitro. These data provide evidence of an epithelial cell-of-origin for TFE3 -driven PEComas, highlighting a reciprocal role for SFPQ-TFE3 and mTOR in driving lineage plasticity in the kidney.