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

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 () and Samvid Kurlekar ()
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Joanna D.C.C. Lima: University of Oxford
Madeleine Hooker: University of Oxford
Ran Li: University of Oxford
Ayslan B. Barros: University of Oxford
Norma Masson: University of Oxford
Christopher W. Pugh: University of Oxford
David R. Mole: University of Oxford
Julie Adam: University of Oxford
Peter J. Ratcliffe: University of Oxford
Samvid Kurlekar: University of Oxford

Nature Communications, 2025, vol. 16, issue 1, 1-18

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-64214-3

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