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 and Tamara L. Lotan ()
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Kaushal Asrani: Johns Hopkins University School of Medicine
Adrianna Amaral: Johns Hopkins University School of Medicine
Juhyung Woo: Johns Hopkins University School of Medicine
Sanaz Nourmohammadi Abadchi: Johns Hopkins University School of Medicine
Thiago Vidotto: Johns Hopkins University School of Medicine
Eddie Imada: Johns Hopkins University School of Medicine
Alyza Skaist: Johns Hopkins University School of Medicine
Kewen Feng: Johns Hopkins University School of Medicine
Hans B. Liu: Johns Hopkins University School of Medicine
Mithila Kasbe: Johns Hopkins University School of Medicine
Yorifumi Satou: Kumamoto University
Masaya Baba: Kumamoto University
Yuichi Oike: Kumamoto University
Patricia Outeda: School of Medicine
Terry Watnick: School of Medicine
Avi Z. Rosenberg: Johns Hopkins University School of Medicine
Laura S. Schmidt: National Institutes of Health
W. Marston Linehan: National Institutes of Health
Pedram Argani: Johns Hopkins University School of Medicine
Tamara L. Lotan: Johns Hopkins University School of Medicine

Nature Communications, 2025, vol. 16, issue 1, 1-23

Abstract: Abstract 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.

Date: 2025
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DOI: 10.1038/s41467-025-63885-2

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