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The Polycomb Repressor Complex 1 Drives Double-Negative Prostate Cancer Metastasis by Coordinating Stemness and Immune Suppression

Authors
 Wenjing Su  ;  Hyun Ho Han  ;  Yan Wang  ;  Boyu Zhang  ;  Bing Zhou  ;  Yuanming Cheng  ;  Alekya Rumandla  ;  Sreeharsha Gurrapu  ;  Goutam Chakraborty  ;  Jie Su  ;  Guangli Yang  ;  Xin Liang  ;  Guocan Wang  ;  Neal Rosen  ;  Howard I Scher  ;  Ouathek Ouerfelli 
Citation
 CANCER CELL, Vol.36(2) : 139-155.e10, 2021-08 
Journal Title
CANCER CELL
ISSN
 1535-6108 
Issue Date
2021-08
MeSH
Adenocarcinoma / drug therapy ; Adenocarcinoma / immunology ; Adenocarcinoma / metabolism* ; Adenocarcinoma / secondary ; Animals ; Antineoplastic Agents, Immunological / pharmacology ; Antineoplastic Combined Chemotherapy Protocols / pharmacology ; Cell Movement* / drug effects ; Cell Self Renewal* / drug effects ; Chemokine CCL2 / genetics ; Chemokine CCL2 / metabolism* ; Enzyme Inhibitors / pharmacology ; Gene Expression Regulation, Neoplastic ; Humans ; Lymphocytes, Tumor-Infiltrating / immunology ; Lymphocytes, Tumor-Infiltrating / metabolism ; Macrophages / immunology ; Macrophages / metabolism ; Male ; Mice, Inbred BALB C ; Mice, Inbred C57BL ; Mice, Inbred NOD ; Mice, Knockout ; Mice, Nude ; Mice, SCID ; Neoplasm Metastasis ; Neoplastic Stem Cells / immunology ; Neoplastic Stem Cells / metabolism* ; Neoplastic Stem Cells / pathology ; PC-3 Cells ; Polycomb Repressive Complex 1 / antagonists & inhibitors ; Polycomb Repressive Complex 1 / genetics ; Polycomb Repressive Complex 1 / metabolism* ; Prostatic Neoplasms / drug therapy ; Prostatic Neoplasms / immunology ; Prostatic Neoplasms / metabolism* ; Prostatic Neoplasms / pathology ; Receptors, Androgen / deficiency ; Receptors, Androgen / genetics ; Receptors, CCR4 / genetics ; Receptors, CCR4 / metabolism ; Signal Transduction ; T-Lymphocytes, Regulatory / immunology ; T-Lymphocytes, Regulatory / metabolism ; Tumor Escape* / drug effects ; Xenograft Model Antitumor Assays
Keywords
MDSCs ; Tregs ; angiogenesis ; combination therapy ; epigenetics ; immune evasion ; immune microenvironment ; metastasis ; preclinical compound ; stemness
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 CCL2 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.
Files in This Item:
T202105265.pdf Download
DOI
10.1016/j.ccell.2019.06.009
Appears in Collections:
1. College of Medicine (의과대학) > Dept. of Urology (비뇨의학교실) > 1. Journal Papers
Yonsei Authors
Han, Hyun Ho(한현호) ORCID logo https://orcid.org/0000-0002-6268-0860
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/187197
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