Tumor heterogeneity in VHL drives metastasis in clear cell renal cell carcinoma

Loss of function of the von Hippel-Lindau (VHL) tumor suppressor gene is a hallmark of clear cell renal cell carcinoma (ccRCC). The importance of heterogeneity in the loss of this tumor suppressor has been under reported. To study the impact of intratumoral VHL heterogeneity observed in human ccRCC, we engineered VHL gene deletion in four RCC models, including a new primary tumor cell line derived from an aggressive metastatic case. The VHL gene-deleted (VHL-KO) cells underwent epithelial-to-mesenchymal transition (EMT) and exhibited increased motility but 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. Combined tumors displayed rampant lung metastases, highlighting a novel cooperative metastatic mechanism. The poorly proliferative VHL-KO cells stimulated the proliferation, EMT, and motility of neighboring VHL+ cells. Periostin (POSTN), a soluble protein overexpressed and secreted by VHL non-expressing (VHL-) cells, promoted metastasis by enhancing the motility of VHL-WT cells and facilitating tumor cell vascular escape. Genetic deletion or antibody blockade of POSTN dramatically suppressed lung metastases in our preclinical models. This work supports a new strategy to halt the progression of ccRCC by disrupting the critical metastatic crosstalk between heterogeneous cell populations within a tumor.

Automated summary

Loss of function of the VHL tumor suppressor gene is a characteristic of ccRCC. Heterogeneity in the loss of this gene is important but often overlooked. By studying intratumoral VHL heterogeneity, the researchers found that VHL gene-deleted cells exhibited increased motility but decreased proliferation and tumorigenicity compared to VHL-expressing cells. Combined tumors with both VHL+ and VHL-KO cells showed rampant lung metastases, driven by the crosstalk between these heterogeneous cell populations. Targeting the soluble protein POSTN, secreted by VHL- cells, could effectively suppress lung metastases. This work suggests a new strategy to disrupt the metastatic crosstalk within tumors and halt the progression of ccRCC.