Macrophage-Derived Cholesterol Contributes to Therapeutic Resistance in Prostate Cancer
Abstract
Castration-resistant prostate cancer (CRPC) is a lethal stage of disease in which androgen receptor (AR) signaling is persistent despite androgen deprivation therapy (ADT). Most studies have focused on investigating cell-autonomous alterations in CRPC, while the contributions of the tumor microenvironment are less well understood. Here we sought to determine the role of tumor-associated macrophages in CRPC, based upon their role in cancer progression and therapeutic resistance. In a syngeneic model that reflected the mutational landscape of CRPC, macrophage depletion resulted in a reduced transcriptional signature for steroid and bile acid synthesis, indicating potential perturbation of cholesterol metabolism. As cholesterol is the precursor of the five major types of steroid hormones, we hypothesized that macrophages were regulating androgen biosynthesis within the prostate tumor microenvironment. Macrophage depletion reduced androgen levels within prostate tumors and restricted AR nuclear localization in vitro and in vivo. Macrophages were also cholesterol-rich and were able to transfer cholesterol to tumor cells in vitro. AR nuclear translocation was inhibited by activation of liver X receptor (LXR)-β, the master regulator of cholesterol homeostasis. Consistent with these data, macrophage depletion extended survival during ADT and the presence of macrophages correlated with therapeutic resistance in patient-derived explants. Taken together, these findings support the therapeutic targeting of macrophages in CRPC.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Jul 23, 2021
- Source ID
- 10.1158/0008-5472.can-20-4028
Entities
People
- Amparo N. Serna
- Asmaa E El-Kenawi
- Aysenur Keske
- Brian Ruffell
- Jasreman Dhillon
- John Koomen
- Julieta Abraham-Miranda
- KayLee K. Steiner
- Kosj Yamoah
- Leenil Noel
- Min Liu
- Robert Gatenby
- Robert J Gillies
- Shivanshu Awasthi
- William Dominguez-viqueira
- Xiaoqing Yu
Organizations
- H. Lee Moffitt Cancer Center & Research Institute
- National Institutes of Health
- United States Department of Defense