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.
The Journal of experimental medicine. 2023 Feb 07 [Epub]
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
Centre for Reproductive Health, College of Medicine and Veterinary Medicine, Queen's Medical Research Institute, The University of Edinburgh , Edinburgh, UK., Human Phenome Institute, Zhangjiang Fudan International Innovation Center, Fudan University , Shanghai, China., Department of Urology, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya Medicine School, Central South University , Changsha, China., Department of Urology, The Second Xiangya Hospital, Central South University , Changsha, China., BGI-Shenzhen , Shenzhen, China., Department of Pharmacy, Peking University First Hospital , Beijing, China., Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center , New York, NY, USA., Edinburgh Cancer Research UK Centre, Institute of Genetics and Cancer, University of Edinburgh , Edinburgh, UK., Centre for Inflammation Research, Queen's Medical Research Institute, University of Edinburgh , Edinburgh, UK., Department of Orthopedics, The Second Affiliated Hospital, School of Medicine, Zhejiang University , Hangzhou, China., Shanghai Jiao Tong University Affiliated Sixth People's Hospital , Shanghai, China.