Abstract
Abstract Castration-resistant prostate cancer (CRPC) is a lethal stage of disease. A wealth of clinical and experimental data supports the persistence of androgen receptor (AR) signaling in many cases of CRPC, despite androgen-deprivation therapy (ADT). Here we sought to determine the role of macrophage cholesterol in CRPC and androgen signaling using a syngeneic model that reflected the mutational landscape of the disease. A transcriptomic analysis of prostate tumors following macrophage depletion revealed lower molecular signatures for steroid and bile acid metabolism, indicating perturbation of cholesterol transport. Since cholesterol is the precursor of steroid hormones, we reasoned that macrophages were regulating androgen biosynthesis within the prostate tumor microenvironment. Indeed, macrophage depletion reduced the levels of androgens within prostate tumors and restricted androgen receptor (AR) nuclear localization in vitro and in vivo. Macrophages were cholesterol rich and had the ability to transfer cholesterol to tumor cells in vitro, and AR nuclear translocation was inhibited by activation of Liver X Receptor (LXR)-β, the master regulator of cholesterol homeostasis. Finally, combining macrophage depletion with androgen deprivation therapy increased survival, supporting the therapeutic potential of targeting macrophages in CRPC. Citation Format: Asmaa El-Kenawi, William Dominguez Viqueira, Min Liu, Shivanshu Awasthi, Jasreman Dhillon, Kosj Yamoah, Xiaoqing Yu, John Koomen, Robert Gatenby, Brian Ruffell. Macrophage tumor cell metabolic interactions induce therapeutic resistance in prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 734.
Published Version
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