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

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

Cioni, Bianca (Netherlands Cancer Institute)
Nevedomskaya, Ekaterina (Netherlands Cancer Institute; Oncode Institute)
Melis, Monique H.M. (Netherlands Cancer Institute)
van Burgsteden, Johan (Netherlands Cancer Institute)
Stelloo, Suzan (Netherlands Cancer Institute; Student TU Delft)
Hodel, Emma (Netherlands Cancer Institute)
Spinozzi, Daniele (Netherlands Cancer Institute)
de Jong, Jeroen (Netherlands Cancer Institute)
Wessels, L.F.A. (TU Delft Pattern Recognition and Bioinformatics; Netherlands Cancer Institute; Oncode Institute)

2018

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.

androgen receptor
cancer cell migration
cancer-associated fibroblasts
CCL2
CXCL8
EMT
prostate cancer

http://resolver.tudelft.nl/uuid:f32ef57f-337b-41a6-9dc0-81ee92f1a726

https://doi.org/10.1002/1878-0261.12327

1574-7891

Molecular Oncology, 12 (8), 1308-1323

Institutional Repository

journal article

© 2018 Bianca Cioni, Ekaterina Nevedomskaya, Monique H.M. Melis, Johan van Burgsteden, Suzan Stelloo, Emma Hodel, Daniele Spinozzi, Jeroen de Jong, L.F.A. Wessels, More Authors