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<p>MiT/TFE gene fusions like <i>SFPQ-TFE3</i> drive both epithelial (translocation RCC) and mesenchymal (PEComas) neoplasms. However, no mouse models for <i>SFPQ-TFE3</i>-related tumors exist and the underlying mechanisms of lineage plasticity remain unclear. Here, we demonstrate that constitutive murine renal expression of <i>SFPQ-TFE3</i> 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, <i>SFPQ-TFE3</i> 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 <i>SFPQ-TFE3</i> expression and rescues PAX8 expression and transcriptional activity in vitro. These data provide evidence of an epithelial cell-of-origin for <i>TFE3</i>-driven PEComas, highlighting a reciprocal role for <i>SFPQ-TFE3</i> and mTOR in driving lineage plasticity in the kidney.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年10月3日

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  • 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,
  • Tamara L. Lotan

摘要

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.