Macrophages promote anti-androgen resistance in prostate cancer bone disease

Xue-feng Li, Cigdem Selli, Han-lin Zhou, Jian Cao, Shuiqing Wu, Ruo-yu Ma, Ye Lu, Cheng-bin Zhang, Bijie Xun, Alyson D. Lam, Xiao-cong Pang, Anu Fernando, Zeda Zhang, Asier Unciti-Broceta, Neil O. Carragher, Prakash Ramachandran, Neil C. Henderson, Ling-ling Sun, Hai-yan Hu, Gui-bo LiCharles Sawyers, Bin-zhi Qian

Research output: Contribution to journalArticlepeer-review

Abstract / Description of output

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
Original languageEnglish
JournalJournal of Experimental Medicine
Issue number4
Early online date7 Feb 2023
Publication statusE-pub ahead of print - 7 Feb 2023


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