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.
Signal transduction and targeted therapy. 2023 Apr 17*** epublish ***
Junhui Hu, Ping Tan, Moe Ishihara, Nicholas A Bayley, Shiruyeh Schokrpur, Jeremy G Reynoso, Yangjun Zhang, Raymond J Lim, Camelia Dumitras, Lu Yang, Steven M Dubinett, Parmjit S Jat, Jacques Van Snick, Jiaoti Huang, Arnold I Chin, Robert M Prins, Thomas G Graeber, Hua Xu, Lily Wu
Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, 90095, USA., Department of Urology, West China Hospital, Chengdu, China., Department of Hematology and Oncology, University of California San Diego, San Diego, CA, 92103, USA., Department of Neurosurgery, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, 90095, USA., Department of Biological Repositories, Department of Urology, Zhongnan Hospital of Wuhan University, Wuhan, China., MRC Prion Unit at UCL, Institute of Prion Diseases, 33 Cleveland Street, London, W1W 7FF, UK., Ludwig Institute for Cancer Research Ltd, Brussels, Belgium., Department of Pathology, Duke University, Durham, NC, USA., Jonsson Comprehensive Cancer Center, David Geffen School of Medicine at UCLA, University of California Los Angeles, Los Angeles, CA, 90095, USA., Department of Biological Repositories, Department of Urology, Zhongnan Hospital of Wuhan University, Wuhan, China. ., Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, 90095, USA. .