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

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  • Kaushal Asrani

    (Johns Hopkins University School of Medicine
    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
    Frederick National Laboratory for Cancer Research)

  • W. Marston Linehan

    (National Institutes of Health)

  • Pedram Argani

    (Johns Hopkins University School of Medicine)

  • Tamara L. Lotan

    (Johns Hopkins University School of Medicine
    Johns Hopkins University School of Medicine
    Johns Hopkins University School of Medicine)

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.

Suggested Citation

  • 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 & Y, 2025. "SFPQ-TFE3 reciprocally regulates mTORC1 and induces lineage plasticity in a mouse model of renal tumorigenesis," Nature Communications, Nature, vol. 16(1), pages 1-23, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-63885-2
    DOI: 10.1038/s41467-025-63885-2
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