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
  • 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.