Fig. 3

Model of tumor initiation and metastasis initiation of ccRCC. Renal stem/progenitor cell (RSPC) experiences chromosome 3p loss and begins a slow clonal expansion, followed by loss of the 2nd VHL allele, and becomes tumor-initiating cells (TICs). Loss of VHL function promotes proliferation, survival, genome instability, and reconstitution of the microenvironment, resulting in subclonal evolution, which mainly produces heterogeneous subclones of benign tumor cells. The subclonal evolution may also be aided by epigenetic changes enhanced by the loss of haploid PBRM1, SETD2, and BAP1. Chromosome 9p21.3 loss and other genetic events such as EMT induction then generate metastasis-initiating cells (MICs)