Abstract
An autochthonous mouse model of clear cell renal cell carcinoma (ccRCC) recapitulates the human disease.
Major finding: An autochthonous mouse model of clear cell renal cell carcinoma (ccRCC) recapitulates the human disease.
Concept: Recurrent mutations in primary cilium–associated genes occur in mouse and human ccRCC.
Impact: The ccRCC mouse model may aid identification of therapies and biomarkers for patients with ccRCC.
Biallelic inactivation of the tumor suppressor gene VHL occurs in the large majority of clear cell renal cell carcinomas (ccRCC) but is insufficient to drive ccRCC tumorigenesis. Other recurrent mutations likely cooperate with VHL inactivation to induce ccRCC. Harlander and colleagues found that human ccRCCs have recurrent copy-number changes in genes that regulate cell-cycle progression, and developed a mouse model of ccRCC in which Vhl, Trp53, and Rb1 were co-deleted in renal epithelial cells. Tumors developed in 82% of VhlΔ/ΔTrp53Δ/ΔRb1Δ/Δ mice within 25–61 weeks of gene deletion. The mouse tumors were molecularly similar to human ccRCCs and exhibited upregulation of HIF1α and HIF2α target genes, genes involved in cell-cycle progression, DNA replication, and mitosis, and genes that regulated immune responses and inflammation. Further, gene expression patterns suggested that ccRCCs in this model arise from the proximal tubule epithelial cells. However, the long latency of tumor onset indicated that additional mutations may be required for tumorigenesis. Exome sequencing of DNA from mouse ccRCCs revealed several amplifications and deletions found in both mouse and human ccRCC, including MYC amplifications. The tumors also had recurrent mutations in genes associated with the primary cilium and tumor cells displayed a reduced frequency of ciliation. Mouse tumors exhibited varying sensitivities to the ccRCC first-line therapy sunitinib; 6 of 19 tumors progressed, 3 regressed, and 10 were stable. Second-line treatment with the mTOR inhibitor everolimus promoted stable disease or regression in 18 of 23 tumors, and inhibition of HIFα signaling with acriflavine slowed tumor growth in 3 of 23 tumors. Altogether, these findings suggest that the VhlΔ/ΔTrp53Δ/ΔRb1Δ/Δ ccRCC autochthonous mouse model recapitulates a subset of the human disease and may aid in the identification of new therapies or biomarkers to predict response to therapies including HIFα inhibitors.
Note: Research Watch is written by Cancer Discovery editorial staff. Readers are encouraged to consult the original articles for full details. For more Research Watch, visit Cancer Discovery online at http://cancerdiscovery.aacrjournals.org/content/early/by/section.