2. Academic Validation
  3. HIFα isoform specific activities drive cell-type specificity of VHL-associated oncogenesis

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

  • Nat Commun. 2025 Oct 16;16(1):9185. doi: 10.1038/s41467-025-64214-3.
Joanna D C C Lima 1 2,  Madeleine Hooker 1 2,  Ran Li 2,  Ayslan B Barros 1 2,  Norma Masson 1 2,  Christopher W Pugh 2,  David R Mole 2,  Julie Adam 1 2,  Peter J Ratcliffe 3 4 5,  Samvid Kurlekar 6 7
Affiliations

Affiliations

  • 1 Ludwig Institute for Cancer Research, Nuffield Department of Medicine, University of Oxford, Oxford, UK.
  • 2 Nuffield Department of Medicine, University of Oxford, Oxford, UK.
  • 3 Ludwig Institute for Cancer Research, Nuffield Department of Medicine, University of Oxford, Oxford, UK. [email protected].
  • 4 Nuffield Department of Medicine, University of Oxford, Oxford, UK. [email protected].
  • 5 The Francis Crick Institute, 1 Midland Road, London, UK. [email protected].
  • 6 Ludwig Institute for Cancer Research, Nuffield Department of Medicine, University of Oxford, Oxford, UK. [email protected].
  • 7 Nuffield Department of Medicine, University of Oxford, Oxford, UK. [email protected].
PMID: 41102155 DOI: 10.1038/s41467-025-64214-3
Abstract

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.

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