PT  - JOURNAL ARTICLE
AU  - Asmaa El-Kenawi
AU  - William Dominguez-Viqueira
AU  - Min Liu
AU  - Shivanshu Awasthi
AU  - Aysenur Keske
AU  - KayLee K. Steiner
AU  - Leenil Noel
AU  - Jasreman Dhillon
AU  - Robert J. Gillies
AU  - Kosj Yamoah
AU  - Xiaoqing Yu
AU  - John Koomen
AU  - Robert A. Gatenby
AU  - Brian Ruffell
TI  - Macrophage-derived cholesterol contributes to therapeutic resistance in prostate cancer
AID  - 10.1101/2021.03.24.436480
DP  - 2021 Jan 01
TA  - bioRxiv
PG  - 2021.03.24.436480
4099  - http://biorxiv.org/content/early/2021/03/24/2021.03.24.436480.short
4100  - http://biorxiv.org/content/early/2021/03/24/2021.03.24.436480.full
AB  - Tumor-associated macrophages are key immune cells associated with cancer progression. Here we sought to determine the role of macrophages in castration-resistant prostate cancer (CRPC) using a syngeneic model that reflected the mutational landscape of the disease. A transcriptomic analysis of CRPC tumors following macrophage depletion revealed lower molecular signatures for steroid and bile acid synthesis, indicating potential perturbation of cholesterol metabolism. Since cholesterol is the precursor of the five major classes 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.Competing Interest StatementA.E., J.K. and B.R. have courtesy faculty appointments at the University of South Florida, Tampa, FL 33620. A.E. has a faculty appointment at Mansoura University, Mansoura Egypt, 35516. B.R. has received payments from Merck & Co., Inc. and Roche Farma S.A. for consulting, and has had sponsored research agreements with TESARO: A GSK Company. The other authors declare no potential conflicts of interest.