2. Academic Validation
  3. SFPQ-TFE3 reciprocally regulates mTORC1 and induces lineage plasticity in a mouse model of renal tumorigenesis

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

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.
PMID: 41044182 DOI: 10.1038/s41467-025-63885-2
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.

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