Discrete genetic effects of 1 VHL and PBRM1 inactivation co-operate to disrupt epithelial homeostasis and promote ccRCC
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Samvid Kurlekar Joanna DCC Lima Niklas Kupfer Christopher W Pugh David R Mole Julie Adam Peter RatcliffeThis article is a preprint. Preprints have not been peer-reviewed.
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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 HIF-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/HIF-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.
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