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. Significance: These results suggest that macrophage-targeted therapies can be combined with androgen deprivation therapy to treat patients with prostate cancer by limiting cholesterol bioavailability and the production of intratumoral androgens. See related commentary by Al-Janabi and Lewis, p. 5399

Lipid-loaded macrophages as new therapeutic target in cancer

“…In this context, TAMs are particularly rich in cholesterol, precursor of steroid hormones that can be transferred to tumor cells, sustaining androgen biosynthesis and tumor resistance to therapies. 96 These findings are in accordance with previous works that confirm the favorable role of cholesterol efflux from murine macrophages for tumor progression. Nevertheless, the authors underline that this efflux affects primarily macrophage polarization, thus pointing out that its inhibition and the subsequent cholesterol accumulation can reprogram macrophages toward a proinflammatory and antitumoral activation.…”

The Roles of Tumor-Associated Macrophages in Prostate Cancer

“…BMDMs can express various genes associated with cholesterol influx/efflux more than the PCa cell lines, including Abcg1, CD36, and Scarb1 [ 127 ]. They could absorb cholesterol in the form of low-density lipoprotein (LDL) and transfer particles containing rich cholesterol into neighboring prostate tumor cells, where it acts as a precursor to enhance androgen biosynthesis for nuclear translocation of AR [ 128 ].…”

Impact of cancer metabolism on therapy resistance – Clinical implications

“…In all these studies, adipocytes have been shown to release free FAs (initially stored as TGs in LDs) that can be taken up and used by cancer cells to support metabolic demands and survival under drug-induced stress conditions. Finally, a lipid-based metabolic cooperation has also been observed between macrophages and prostate cancer cells to support therapy resistance (El-Kenawi et al, 2021). The authors have observed that macrophages can transfer cholesterol to tumor cells in vitro, supporting a persistent androgen receptor signaling despite androgen deprivation therapy (ADT).…”