Macrophages promote anti-androgen resistance in prostate cancer bone disease
© 2023 Li et al..
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.
| Errataetall: | |
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| Medienart: |
E-Artikel |
| Erscheinungsjahr: |
2023 |
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| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:220 |
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| Enthalten in: |
The Journal of experimental medicine - 220(2023), 4 vom: 03. Apr. |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Li, Xue-Feng [VerfasserIn] |
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| Links: |
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| Themen: |
Androgen Antagonists |
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| Anmerkungen: |
Date Completed 09.02.2023 Date Revised 28.03.2024 published: Print-Electronic CommentIn: J Exp Med. 2023 Apr 3;220(4):. - PMID 36828392 Citation Status MEDLINE |
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| doi: |
10.1084/jem.20221007 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM352597402 |
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| 100 | 1 | |a Li, Xue-Feng |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Macrophages promote anti-androgen resistance in prostate cancer bone disease |
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| 500 | |a CommentIn: J Exp Med. 2023 Apr 3;220(4):. - PMID 36828392 | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a © 2023 Li et al. | ||
| 520 | |a 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 | ||
| 650 | 4 | |a Journal Article | |
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| 650 | 7 | |a Receptors, Androgen |2 NLM | |
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| 700 | 1 | |a Zhou, Han-Lin |e verfasserin |4 aut | |
| 700 | 1 | |a Cao, Jian |e verfasserin |4 aut | |
| 700 | 1 | |a Wu, Shuiqing |e verfasserin |4 aut | |
| 700 | 1 | |a Ma, Ruo-Yu |e verfasserin |4 aut | |
| 700 | 1 | |a Lu, Ye |e verfasserin |4 aut | |
| 700 | 1 | |a Zhang, Cheng-Bin |e verfasserin |4 aut | |
| 700 | 1 | |a Xun, Bijie |e verfasserin |4 aut | |
| 700 | 1 | |a Lam, Alyson D |e verfasserin |4 aut | |
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| 700 | 1 | |a Zhang, Zeda |e verfasserin |4 aut | |
| 700 | 1 | |a Unciti-Broceta, Asier |e verfasserin |4 aut | |
| 700 | 1 | |a Carragher, Neil O |e verfasserin |4 aut | |
| 700 | 1 | |a Ramachandran, Prakash |e verfasserin |4 aut | |
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| 700 | 1 | |a Qian, Bin-Zhi |e verfasserin |4 aut | |
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