Macrophages promote anti-androgen resistance in prostate cancer bone disease Journal Article
| Authors: | Li, X. F.; Selli, C.; Zhou, H. L.; Cao, J.; Wu, S.; Ma, R. Y.; Lu, Y.; Zhang, C. B.; Xun, B.; Lam, A. D.; Pang, X. C.; Fernando, A.; Zhang, Z.; Unciti-Broceta, A.; Carragher, N. O.; Ramachandran, P.; Henderson, N. C.; Sun, L. L.; Hu, H. Y.; Li, G. B.; Sawyers, C.; Qian, B. Z. |
| Article Title: | Macrophages promote anti-androgen resistance in prostate cancer bone disease |
| Abstract: | Metastatic castration-resistant prostate cancer (PC) is the final stage of PC that acquires resistance to androgen deprivation therapies (ADT). Despite progresses in understanding of disease mechanisms, the specific contribution of the metastatic microenvironment to ADT resistance remains largely unknown. The current study identified that the macrophage is the major microenvironmental component of bone-metastatic PC in patients. Using a novel in vivo model, we demonstrated that macrophages were critical for enzalutamide resistance through induction of a wound-healing–like response of ECM–receptor gene expression. Mechanistically, macrophages drove resistance through cytokine activin A that induced fibronectin (FN1)-integrin alpha 5 (ITGA5)–tyrosine kinase Src (SRC) signaling cascade in PC cells. This novel mechanism was strongly supported by bioinformatics analysis of patient transcriptomics datasets. Furthermore, macrophage depletion or SRC inhibition using a novel specific inhibitor significantly inhibited resistant growth. Together, our findings elucidated a novel mechanism of macrophage-induced anti-androgen resistance of metastatic PC and a promising therapeutic approach to treat this deadly disease. © 2023 Li et al. |
| Journal Title: | Journal of Experimental Medicine |
| Volume: | 220 |
| Issue: | 4 |
| ISSN: | 0022-1007 |
| Publisher: | Rockefeller University Press |
| Date Published: | 2023-04-03 |
| Start Page: | e20221007 |
| Language: | English |
| DOI: | 10.1084/jem.20221007 |
| PROVIDER: | scopus |
| PMCID: | PMC9948761 |
| PUBMED: | 36749798 |
| DOI/URL: | |
| Notes: | Article -- MSK corresponding author is Charles Sawyers -- Export Date: 1 June 2023 -- Source: Scopus |
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