Intratumoral heterogeneity of VHL drives metastasis in clear cell renal cell carcinoma through a cooperative mechanism where VHL-knockout cells secrete periostin to promote the motility of VHL-wildtype cells.
Does intratumoral VHL heterogeneity and POSTN secretion drive metastasis in clear cell renal cell carcinoma?
Intratumoral VHL heterogeneity promotes ccRCC metastasis via POSTN secretion, suggesting POSTN blockade as a potential therapeutic strategy to halt progression.
Abstract 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.
Hu et al. (Mon,) conducted a other in Clear cell renal cell carcinoma (n=26). VHL gene deletion and POSTN blockade vs. VHL-wildtype cells was evaluated on Metastasis and tumor growth. Intratumoral heterogeneity of VHL drives metastasis in clear cell renal cell carcinoma through a cooperative mechanism where VHL-knockout cells secrete periostin to promote the motility of VHL-wildtype cells.