Combined mutation in Vhl, Trp53 and Rb1 causes clear cell renal cell carcinoma in mice

• Published in: Nature medicine Vol. 23; no. 7; pp. 869 - 877
• Main Authors: Harlander, Sabine, Schönenberger, Désirée, Toussaint, Nora C, Prummer, Michael, Catalano, Antonella, Brandt, Laura, Moch, Holger, Wild, Peter J, Frew, Ian J
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01-07-2017; Nature Publishing Group
• Subjects: 13/51; 38; 38/91; 45/23; 59; 631/67/589/1588/1351; 631/67/70; 64/60; Acriflavine; Animals; Biomedicine; Cancer; Cancer Research; Carcinoma, Renal Cell - genetics; Cell cycle; Cilia - genetics; Clear cell-type renal cell carcinoma; Clonal deletion; Convergence; Deactivation; Disease Models, Animal; DNA binding proteins; Epithelial Cells; Gene expression; Gene mutation; Gene sequencing; Genes; Genetic aspects; Human behavior; Humans; Hypoxia; Hypoxia-Inducible Factor 1, alpha Subunit - metabolism; Hypoxia-inducible factors; Immunohistochemistry; Inactivation; Infectious Diseases; Kaplan-Meier Estimate; Kidney cancer; Kidney Neoplasms - genetics; Kidney Tubules, Proximal - cytology; Kidneys; Markers; Metabolic Diseases; Mice; Mimicry; Molecular Medicine; Mutation; Neoplasia; Neurosciences; Renal cell carcinoma; Retinoblastoma; Retinoblastoma Binding Proteins - genetics; Retinoblastoma Protein - genetics; RNA; RNA, Messenger - metabolism; Rodents; Survival Rate; Transcription factors; Tumor Suppressor Protein p53 - genetics; Tumors; Ubiquitin-Protein Ligases - genetics; VHL protein; Von Hippel-Lindau Tumor Suppressor Protein - genetics; X-Ray Microtomography
• ISSN: 1078-8956; 1546-170X
• DOI: 10.1038/nm.4343

Through combined deletion of
Vhl
,
Trp53
and
Rb1
in renal epithelial cells, the authors develop a new mouse model of renal cell carcinoma that recapitulates the cellular and molecular features of a large proportion of human tumors. This model uncovers a role for primary-cilium-related genes in the development of the disease and provides a reliable platform for preclinical therapeutic studies.
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.