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<p>Cancers arising from dysregulation of generally operative signaling pathways are often tissue specific, but the mechanisms underlying this paradox are poorly understood. Based on striking cell-type specificity, we postulated that these mechanisms must operate early in cancer development and set out to study them in a model of von Hippel Lindau (VHL) disease. Biallelic mutation of the VHL ubiquitin ligase leads to constitutive activation of hypoxia inducible factors HIF1A and HIF2A and is generally a truncal event in clear cell renal carcinoma. We used an oncogenic tagging strategy in which <i>VHL</i>-mutant cells are marked by tdTomato, enabling their observation, retrieval, and analysis early after <i>VHL</i>-inactivation. Here, we reveal markedly different consequences of HIF1A and HIF2A activation, but that both contribute to renal cell-type specific consequences of <i>VHL</i>-inactivation in the kidney. Early involvement of HIF2A in promoting proliferation within the&#xa0;proximal tubular epithelium supports therapeutic targeting of HIF2A early in VHL disease.</p>

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HIFα isoform specific activities drive cell-type specificity of VHL-associated oncogenesis

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年10月16日

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  • Joanna D.C.C. Lima,
  • Madeleine Hooker,
  • Ran Li,
  • Ayslan B. Barros,
  • Norma Masson,
  • Christopher W. Pugh,
  • David R. Mole,
  • Julie Adam,
  • Peter J. Ratcliffe,
  • Samvid Kurlekar

摘要

Cancers arising from dysregulation of generally operative signaling pathways are often tissue specific, but the mechanisms underlying this paradox are poorly understood. Based on striking cell-type specificity, we postulated that these mechanisms must operate early in cancer development and set out to study them in a model of von Hippel Lindau (VHL) disease. Biallelic mutation of the VHL ubiquitin ligase leads to constitutive activation of hypoxia inducible factors HIF1A and HIF2A and is generally a truncal event in clear cell renal carcinoma. We used an oncogenic tagging strategy in which VHL-mutant cells are marked by tdTomato, enabling their observation, retrieval, and analysis early after VHL-inactivation. Here, we reveal markedly different consequences of HIF1A and HIF2A activation, but that both contribute to renal cell-type specific consequences of VHL-inactivation in the kidney. Early involvement of HIF2A in promoting proliferation within the proximal tubular epithelium supports therapeutic targeting of HIF2A early in VHL disease.