Approximately half of all clear cell renal cell carcinoma (ccRCC) patients develop metastases, predominantly in the bones, lungs and brain and the prognosis for these patients is very poor. The development of new therapies requires a better understanding of the cellular and molecular alterations that underlie metastatic dissemination and growth, which for ccRCC is currently extremely limited. Based upon studies of the two most frequently mutated genes in human ccRCC, the VHL and PBRM1 tumor suppressor genes, we aim to develop a series of metastatic xenograft models using genetically engineered human ccRCC cells. Through cell biological studies, genome-wide epigenetic analyses, RNA sequencing and in vivo functional genetic screening approaches, we are characterizing the involvement of epigenetic dysregulation of VHL and PBRM1-regulated target genes in different aspects of the metastatic process, including cellular adhesion, migration, invasion, dissemination and growth at secondary sites. We also seek to assess the relevance of our studies to the human disease by analyzing primary tumors and metastases from patients with ccRCC. These studies are being complemented by a mouse genetic tumour modelling approach and by shRNA library screening approaches to identify other epigenetic modulators that cooperate with loss of VHL function to enhance motility, invasion and metastasis.