1. The Polycomb Repressor Complex 1 Drives Double-Negative Prostate Cancer Metastasis by Coordinating Stemness and Immune Suppression.
- Author
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Su, Wenjing, Han, Hyun Ho, Wang, Yan, Zhang, Boyu, Zhou, Bing, Cheng, Yuanming, Rumandla, Alekya, Gurrapu, Sreeharsha, Chakraborty, Goutam, Su, Jie, Yang, Guangli, Liang, Xin, Wang, Guocan, Rosen, Neal, Scher, Howard I., Ouerfelli, Ouathek, and Giancotti, Filippo G.
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PROGRAMMED cell death 1 receptors , *METASTASIS , *IMMUNOSUPPRESSION , *PROSTATE cancer - Abstract
The mechanisms that enable immune evasion at metastatic sites are poorly understood. We show that the Polycomb Repressor Complex 1 (PRC1) drives colonization of the bones and visceral organs in double-negative prostate cancer (DNPC). In vivo genetic screening identifies CCL 2 as the top prometastatic gene induced by PRC1. CCL2 governs self-renewal and induces the recruitment of M2-like tumor-associated macrophages and regulatory T cells, thus coordinating metastasis initiation with immune suppression and neoangiogenesis. A catalytic inhibitor of PRC1 cooperates with immune checkpoint therapy to reverse these processes and suppress metastasis in genetically engineered mouse transplantation models of DNPC. These results reveal that PRC1 coordinates stemness with immune evasion and neoangiogenesis and point to the potential clinical utility of targeting PRC1 in DNPC. • PRC1 promotes metastatic outgrowth by inducing expression of CCL2 • CCL2 promotes self-renewal by binding to CCR4 on prostate cancer cells • CCL2 recruits M2-like TAMs and Tregs, inducing immune suppression and angiogenesis • PRC1 inhibitor cooperates with checkpoint immunotherapy to suppress metastasis Su et al. show that PRC1 drives metastasis of androgen receptor and neuroendocrine double-negative prostate cancers by regulating CCL2 expression. CCL2 governs self-renewal and recruitment of TAM and Treg. PRC1 inhibition combined with immune checkpoint blockade reverses these processes and suppresses metastasis. [ABSTRACT FROM AUTHOR]
- Published
- 2019
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