Loss of androgen receptor signaling in prostate cancer-associated fibroblasts (CAFs) promotes CCL2- and CXCL8-mediated cancer cell migration

Fibroblasts are abundantly present in the prostate tumor microenvironment (TME), including cancer-associated fibroblasts (CAFs) which play a key role in cancer development. Androgen receptor (AR) signaling is the main driver of prostate cancer (PCa) progression, and stromal cells in the TME also express AR. High-grade tumor and poor clinical outcome are associated with low AR expression in the TME, which suggests a protective role of AR signaling in the stroma against PCa development. However, the mechanism of this relation is not clear. In this study, we isolated AR-expressing CAF-like cells. Testosterone (R1881) exposure did not affect CAF-like cell morphology, proliferation, or motility. PCa cell growth was not affected by culturing in medium from R1881-exposed CAF-like cells; however, migration of PCa cells was inhibited. AR chromatin immune precipitation sequencing (ChIP-seq) was performed and motif search suggested that AR in CAF-like cells bound the chromatin through AP-1-elements upon R1881 exposure, inducing enhancer-mediated AR chromatin interactions. The vast majority of chromatin binding sites in CAF-like cells were unique and not shared with AR sites observed in PCa cell lines or tumors. AR signaling in CAF-like cells decreased expression of multiple cytokines; most notably CCL2 and CXCL8 and both cytokines increased migration of PCa cells. These results suggest direct paracrine regulation of PCa cell migration by CAFs through AR signaling.Pattern Recognition and Bioinformatic

Androgen receptor signalling in macrophages promotes TREM-1-mediated prostate cancer cell line migration and invasion

The androgen receptor (AR) is the master regulator of prostate cancer (PCa) development, and inhibition of AR signalling is the most effective PCa treatment. AR is expressed in PCa cells and also in the PCa-associated stroma, including infiltrating macrophages. Macrophages have a decisive function in PCa initiation and progression, but the role of AR in macrophages remains largely unexplored. Here, we show that AR signalling in the macrophage-like THP-1 cell line supports PCa cell line migration and invasion in culture via increased Triggering Receptor Expressed on Myeloid cells-1 (TREM-1) signalling and expression of its downstream cytokines. Moreover, AR signalling in THP-1 and monocyte-derived macrophages upregulates IL-10 and markers of tissue residency. In conclusion, our data suggest that AR signalling in macrophages may support PCa invasiveness, and blocking this process may constitute one mechanism of anti-androgen therapy