Clear cell renal cell carcinomas (ccRCCs) frequently exhibit inactivation of the von Hippel–Lindau tumor-suppressor gene, VHL, and often harbor multiple copy-number alterations in genes that regulate cell cycle progression. We show here that modeling these genetic alterations by combined deletion of Vhl, Trp53 and Rb1 specifically in renal epithelial cells in mice caused ccRCC. These tumors arose from proximal tubule epithelial cells and shared molecular markers and mRNA expression profiles with human ccRCC. Exome sequencing revealed that mouse and human ccRCCs exhibit recurrent mutations in genes associated with the primary cilium, uncovering a mutational convergence on this organelle and implicating a subset of ccRCCs as genetic ciliopathies. Different mouse tumors responded differently to standard therapies for advanced human ccRCC, mimicking the range of clinical behaviors in the human disease. Inhibition of hypoxia-inducible factor (HIF)-α transcription factors with acriflavine as third-line therapy had therapeutic effects in some tumors, providing preclinical evidence for further investigation of HIF-α inhibition as a ccRCC treatment. This autochthonous mouse ccRCC model represents a tool to investigate the biology of ccRCC and to identify new treatment strategies.
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This work was supported by grants to I.J.F. from the Swiss National Science Foundation (PP00P3_128257), the European Research Council (260316) and the VHL Family Alliance. We are most grateful to Johannes Loffing (University of Zurich), Jürg Biber (University of Zurich) and the late Patrick Pollard (University of Oxford) for providing antibodies.
The authors declare no competing financial interests.
Supplementary Figures 1–9. (PDF 18589 kb)
RNA sequencing analysis of normal kidney cortices and mouse ccRCCs. (XLSX 4548 kb)
Copy number variations in mouse ccRCCs. (XLSX 68 kb)
Collation of high impact mutations and high VAF SNVs in mouse ccRCC tumours. (XLSX 68 kb)
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Harlander, S., Schönenberger, D., Toussaint, N. et al. Combined mutation in Vhl, Trp53 and Rb1 causes clear cell renal cell carcinoma in mice. Nat Med 23, 869–877 (2017). https://doi.org/10.1038/nm.4343