SFPQ-TFE3 reciprocally regulates mTORC1 and induces lineage plasticity in a mouse model of renal tumorigenesis PMID: 41044182

ADC Targets in Oncology

2026-04-10

SFPQ-TFE3 reciprocally regulates mTORC1 and induces lineage plasticity in a mouse model of renal tumorigenesis

Nat Commun. 2025 Oct 3;16(1):8822. doi: 10.1038/s41467-025-63885-2.

Kaushal Asrani ^# ¹ ² , Adrianna Amaral ^# ³ , Juhyung Woo ³ , Sanaz Nourmohammadi Abadchi ³ , Thiago Vidotto ³ , Eddie Imada ⁴ , Alyza Skaist ⁵ , Kewen Feng ⁵ , Hans B Liu ³ , Mithila Kasbe ³ , Yorifumi Satou ⁶ , Masaya Baba ⁷ , Yuichi Oike ⁸ , Patricia Outeda ⁹ , Terry Watnick ⁹ , Avi Z Rosenberg ³ , Laura S Schmidt ¹⁰ ¹¹ , W Marston Linehan ¹⁰ , Pedram Argani ³ , Tamara L Lotan ¹² ¹³ ¹⁴

Affiliations

1. Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA. [email protected].
2. Department of Urology, Johns Hopkins University School of Medicine, Baltimore, MD, USA. [email protected].
3. Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
4. Department of Urology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
5. Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
6. Division of Genomics and Transcriptomics, Kumamoto University, Kumamoto, Japan.
7. Department of Urology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.
8. Department of Molecular Genetics, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.
9. University of Maryland, School of Medicine, Baltimore, MD, USA.
10. Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
11. Basic Science Program, Frederick National Laboratory for Cancer Research, Frederick, MD, USA.
12. Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA. [email protected].
13. Department of Urology, Johns Hopkins University School of Medicine, Baltimore, MD, USA. [email protected].
14. Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA. [email protected].
# Contributed equally.

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.