Macrophages promote anti-androgen resistance in prostate cancer bone disease

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. New mechanism of macrophage-driven therapy resistance of metastatic prostate cancer with high ECM expression and SRC activation using a novel in vivo model of bone-metastatic prostate cancer.

Automated summary

This study identified macrophages as the major component of the metastatic microenvironment in bone-metastatic prostate cancer. Macrophages were found to play a critical role in enzalutamide resistance through the induction of a wound-healing-like response and activation of the cytokine activin A- fibronectin-integrin alpha 5-tyrosine kinase Src signaling cascade. Depletion of macrophages or inhibition of Src significantly inhibited resistant growth, suggesting a potential therapeutic approach for treating metastatic prostate cancer.