Tumor Heterogeneity in VHL Drives Metastasis in Clear Cell Renal Cell Carcinoma

Abstract To study the impact of intratumoral VHL heterogeneity observed in patient ccRCC primary tumors, we engineered VHL gene deletion in three RCC models, including a new primary tumor cell line derived from an aggressive metastatic ccRCC. The VHL gene-deleted (VHL-KO) cells underwent epithelial-to-mesenchymal transition (EMT) and showed diminished proliferation and tumorigenicity compared to the parental, VHL-expressing (VHL+) cells. Renal tumors with either VHL+ or VHL-KO cells alone exhibit minimal metastatic potential. Interestingly, tumors with both cells displayed rampant lung metastasis, highlighting a novel cooperative metastatic mechanism. The poorly proliferative VHL-KO cells stimulated the proliferation, EMT and motility of neighboring VHL+ cells. We found that periostin (POSTN), a protein product overexpressed and secreted by VHL- cells, promoted metastasis by enhancing the motility of VHL-WT cells and facilitating vascular escape of tumor cells. Genetic deletion or antibody blockade of POSTN dramatically suppressed lung metastases in our preclinical models. Our work suggests a new strategy to halt progression in ccRCC by disrupting the critical metastatic crosstalk between heterogeneous cell populations within a tumor.