This study is the first to use CRISPR-mediated technologies to explore the biology of VHL loss driving RCC aggressiveness in a new murine model and has produced intriguing clues regarding the involvement of HIF-1α in metastatic dissemination, new potential marker genes to assess poor prognosis of clinical ccRCC and possible molecular targets to combat mRCC aggressiveness. Here, VHL is linked to renal cell carcinoma.