Back to publications

2026

bioRxiv 2026 Feb 20. doi: 10.64898/2026.02.18.706657

Discrete genetic effects of VHL and PBRM1 inactivation co-operate to disrupt epithelial homeostasis and promote ccRCC

Samvid Kurlekar, Joanna D.C.C. Lima*, Niklas Kupfer, Christopher W. Pugh, David R. Mole, Julie Adam, Peter J. Ratcliffe

Ludwig Institute for Cancer Research, Nuffield Department of Medicine, University of Oxford, Oxford OX3 7FZ, UK. Nuffield Department of Medicine, University of Oxford, Oxford, UK. The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK.

Service type: Knock-in mice

Abstract

Inactivation of VHL is a truncal alteration in clear cell renal cell carcinoma, but additional events are required for oncogenesis, most commonly PBRM1 inactivation. To better understand this co-operation, we used an oncogenic cell-tagging strategy to analyze the earliest transcriptional and cellular consequences of Vhl and/or Pbrm1 inactivation in the renal tubular epithelium, in vivo, at single-cell resolution. Pbrm1 inactivation did not globally alter HIF32 dependent transcription or increase early tubular proliferation induced by Vhl inactivation. Instead, it had independent effects on epithelial organization. Combined genetic and morphological analyses suggested that Pbrm1 inactivation allows cells to sustain Vhl/HIF35 dependent proliferation by disrupting tubular architectures that ordinarily restrain this proliferation, resulting in extra-tubular cell accumulation, multilayered epithelia, and tumor formation. Our findings frame a new model for the VHL-PBRM1 interaction that explains loss of epithelial homeostasis through an interaction between discrete effects that drive proliferation and remove structural tissue restraints on that proliferation.