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

• Published in: Signal transduction and targeted therapy Vol. 8; no. 1; p. 155
• Main Authors: Hu, Junhui, Tan, Ping, Ishihara, Moe, Bayley, Nicholas A, Schokrpur, Shiruyeh, Reynoso, Jeremy G, Zhang, Yangjun, Lim, Raymond J, Dumitras, Camelia, Yang, Lu, Dubinett, Steven M, Jat, Parmjit S, Van Snick, Jacques, Huang, Jiaoti, Chin, Arnold I, Prins, Robert M, Graeber, Thomas G, Xu, Hua, Wu, Lily
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 17.04.2023; Nature Publishing Group UK
• Subjects: Carcinoma, Renal Cell - genetics; Carcinoma, Renal Cell - pathology; Cell proliferation; Clear cell-type renal cell carcinoma; Clonal deletion; Gene deletion; Genes, Tumor Suppressor; Humans; Kidney cancer; Kidney Neoplasms - genetics; Kidney Neoplasms - pathology; Lung Neoplasms - genetics; Metastases; Metastasis; Motility; Tumor suppressor genes; Tumorigenicity; Tumors; VHL protein; Von Hippel-Lindau Tumor Suppressor Protein - genetics
• ISSN: 2059-3635; 2095-9907; 2059-3635
• DOI: 10.1038/s41392-023-01362-2

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.