Wnt5a induces and maintains prostate cancer cells dormancy in bone.

In a substantial fraction of prostate cancer (PCa) patients, bone metastasis appears after years or even decades of latency. Canonical Wnt/β-catenin signaling has been proposed to be implicated in dormancy of cancer cells. However, how these tumor cells are kept dormant and recur under control of Wnt/β-catenin signaling derived from bone microenvironment remains unknown. Here, we report that Wnt5a from osteoblastic niche induces dormancy of PCa cells in a reversible manner in vitro and in vivo via inducing Siah E3 Ubiquitin Protein Ligase 2 (SIAH2) expression, which represses Wnt/β-catenin signaling. Furthermore, this effect of Wnt5a-induced dormancy of PCa cells depends on receptor tyrosine kinase-like orphan receptor 2 (ROR2), and a negative correlation of ROR2 expression with bone metastasis-free survival is observed in PCa patients. Therefore, these results demonstrate that Wnt5a/ROR2/SIAH2 signaling axis plays a crucial role in inducing and maintaining PCa cells dormancy in bone, suggesting a potential therapeutic utility of Wnt5a via inducing dormancy of PCa cells in bone.

The Journal of experimental medicine. 2018 Dec 28 [Epub ahead of print]

Dong Ren, Yuhu Dai, Qing Yang, Xin Zhang, Wei Guo, Liping Ye, Shuai Huang, Xu Chen, Yingrong Lai, Hong Du, Chuyong Lin, Xinsheng Peng, Libing Song

Department of Orthopedic Surgery, the First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China., Department of Experimental Research, State Key Laboratory of Oncology in Southern China, Sun Yat-sen University Cancer Center, Guangzhou, China., Department of Urology, the First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China., Department of Pathology, the First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China., Department of Pathology, the First People's Hospital of Guangzhou City, Guangzhou, China., Department of Orthopedic Surgery, the First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China ., Department of Experimental Research, State Key Laboratory of Oncology in Southern China, Sun Yat-sen University Cancer Center, Guangzhou, China .