SFPQ-TFE3 reciprocally regulates mTORC1 and induces lineage plasticity in a mouse model of renal tumorigenesis
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.
Authors
- Pedram Argani (ORCID: https://orcid.org/0000-0001-8797-9474)
- Tamara L. Lotan (ORCID: https://orcid.org/0000-0002-0494-9067)
- Hans B. Liu (ORCID: https://orcid.org/0000-0001-8911-5637)
- Kaushal Asrani (ORCID: https://orcid.org/0000-0002-9777-5296)
- Yuichi Oike (ORCID: https://orcid.org/0000-0003-3245-5395)
- Eddie L. Imada (ORCID: https://orcid.org/0000-0001-9527-3703)
- Avi Z. Rosenberg (ORCID: https://orcid.org/0000-0003-2356-950X)
- Alyza Skaist
- Kewen Feng
- Patricia Outeda (ORCID: https://orcid.org/0000-0002-0015-9228)
- Juhyung Woo (ORCID: https://orcid.org/0000-0001-6262-8088)
- Thiago Vidotto (ORCID: https://orcid.org/0000-0002-7268-4494)
- Masaya Baba (ORCID: https://orcid.org/0000-0002-5308-6683)
- Adrianna A. Mendes (ORCID: https://orcid.org/0000-0001-8771-7001)
- Yorifumi Satou (ORCID: https://orcid.org/0000-0002-1495-7810)
- Sanaz Nourmohammadi Abadchi (ORCID: https://orcid.org/0000-0003-2167-7793)
- Terry Watnick (ORCID: https://orcid.org/0000-0003-0812-7279)
- Laura S. Schmidt (ORCID: https://orcid.org/0000-0002-5050-5491)
- W. Marston Linehan (ORCID: https://orcid.org/0000-0001-7983-3109)
- Mithila Kasbe
Institutions
- University of Maryland, Baltimore (US)
- National Institutes of Health (US)
- Johns Hopkins University (US)
- Johns Hopkins Medicine (US)
- Frederick National Laboratory for Cancer Research (US)
- National Cancer Institute (US)
- Center for Cancer Research (US)
- Kumamoto University (JP)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-10-03
- DOI
- https://doi.org/10.1038/s41467-025-63885-2
- Citations
- 4
- Primary Topic
- Renal and related cancers
- Type
- article
- Field-Weighted Citation Impact
- 3.22