TY - JOUR
T1 - Macrophages promote anti-androgen resistance in prostate cancer bone disease
AU - Li, Xue-feng
AU - Selli, Cigdem
AU - Zhou, Han-lin
AU - Cao, Jian
AU - Wu, Shuiqing
AU - Ma, Ruo-yu
AU - Lu, Ye
AU - Zhang, Cheng-bin
AU - Xun, Bijie
AU - Lam, Alyson D.
AU - Pang, Xiao-cong
AU - Fernando, Anu
AU - Zhang, Zeda
AU - Unciti-Broceta, Asier
AU - Carragher, Neil O.
AU - Ramachandran, Prakash
AU - Henderson, Neil C.
AU - Sun, Ling-ling
AU - Hu, Hai-yan
AU - Li, Gui-bo
AU - Sawyers, Charles
AU - Qian, Bin-zhi
N1 - Funding Information:
Disclosures: J. Cao was sponsored by China Scholarship Council. A. Unciti-Broceta and N.O. Carragher reported grants from Nuvectis Pharma outside the submitted work; in addition, A. Unciti-Broceta and N.O. Carragher had patents to EP3298015B1, JP6684831B2, US10294227B2, CN107849050B, and CA3021550A1 licensed (Nuvectis Pharma). C. Sawyers reported personal fees from Novartis, Blueprint, Beigene, Foghorn, PMV, KSQ, Housey, Nextech, Column Group, Cellcarta, and Oric outside the submitted work; in addition, C. Sawyers had a patent to enzaluta-mide with royalties paid and a patent to apalutamide with royalties paid. B.Z. Qian reported personal fees from Medanexx Ltd and Nuvectis Pharma outside the submitted work. No other disclosures were reported.
Funding Information:
This work is supported by European Research Council Starting Grant 716379 to B.Z. Qian. N.C. Henderson is supported by a Wellcome Trust Senior Research Fellowship in Clinical Science (ref. 219542/Z/19/Z). R.Y. Ma is supported by the Fellowship of China Postdoctoral Science Foundation (2021M700814), the International Postdoctoral Exchange Fellowship Program (YJ20210251), and the Natural Science Foundation of China (81872150).
Publisher Copyright:
© 2023 Li et al.
PY - 2023/2/7
Y1 - 2023/2/7
N2 - 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
AB - 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
U2 - 10.1084/jem.20221007
DO - 10.1084/jem.20221007
M3 - Article
SN - 0022-1007
VL - 220
JO - Journal of Experimental Medicine
JF - Journal of Experimental Medicine
IS - 4
ER -