Dr. Asmaa El-Kenawi, a member of the Cancer Epidemiology Department, presented a poster session on Macrophage tumor cell metabolic interactions that induce therapeutic resistance in prostate cancer at the AACR 2021 annual meeting.
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).
The focus of the study is 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,” said Dr. El-Kenawi. 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.
View the poster for more information about this study.