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.

• Authors: 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 Li, Charles Sawyers, Bin-Zhi Qian
• Journal: The Journal of experimental medicine (J Exp Med) Vol. 220 Issue 4 (04 03 2023) ISSN: 1540-9538 [Electronic] United States
• PMID: 36749798 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2023 Li et al.

Chemical References

• Androgen Antagonists
• Receptors, Androgen
• Nitriles

Topics

• Male
• Humans
• Androgen Antagonists (therapeutic use)
• Prostatic Neoplasms, Castration-Resistant (drug therapy, metabolism, pathology)
• Cell Line, Tumor
• Macrophages (metabolism)
• Bone Neoplasms
• Receptors, Androgen (genetics)
• Nitriles (therapeutic use)
• Tumor Microenvironment