To investigate acquisition of metastatic potential in RCC, we engineered combinations of tissue-specific somatic knockouts of murine orthologs of the most common tumor suppressor genes (TSGs) driving RCC progression (Vhl, Nf2, Setd2, Bap1 and Trp53), via renal subcapsular administration of adeno-associated viral (AAV) particles carrying single-guide RNAs (sgRNAs) targeting the renal epithelium of mice expressing a tissue-specific conditional Cas9 allele and fluorescent reporters for tracing purposes (Fig. 1a–d). Here, SETD2 is linked to renal cell carcinoma.