Macrophages promote anti-androgen resistance in prostate cancer bone disease.
Macrophages promote anti-androgen resistance in prostate cancer bone disease.
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DOI：
10.1084/jem.20221007
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发表时间：
2023-04-03
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影响因子：
--
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巨噬细胞驱动的转移性前列腺癌治疗抗性的新机制，具有高ECM表达和SRC活化，使用骨转移性前列腺癌的新型体内模型。转移性去势抵抗性前列腺癌（PC）是PC的最后阶段，对雄激素剥夺疗法（ADT）产生抵抗。尽管对疾病机制的理解取得了进展，但转移性微环境对ADT耐药的具体贡献在很大程度上仍然未知。目前的研究表明，巨噬细胞是骨转移性PC患者的主要微环境成分。使用一种新的体内模型，我们证明了巨噬细胞通过诱导ECM受体基因表达的伤口愈合样反应对Enzalutamide耐药至关重要。从机制上讲，巨噬细胞通过细胞因子激活素A诱导PC细胞中的纤连蛋白（FN 1）-整合素α 5（ITGA 5）-酪氨酸激酶Src（SRC）信号级联反应来驱动耐药性。这种新的机制得到了患者转录组数据集的生物信息学分析的有力支持。此外，使用新型特异性抑制剂的巨噬细胞耗竭或SRC抑制显著抑制抗性生长。总之，我们的研究结果阐明了巨噬细胞诱导的转移性PC抗雄激素抵抗的新机制，以及治疗这种致命疾病的有希望的治疗方法。
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. 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.
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影响因子：
64.8
作者：
Cao, Junyue;Spielmann, Malte;Shendure, Jay
通讯作者：
Shendure, Jay
影响因子：
46.9
作者：
Becht, Etienne;McInnes, Leland;Newell, Evan W.
通讯作者：
Newell, Evan W.
LY6C+“炎症单核细胞”是在西尼罗河病毒脑炎中以致病方式募集的小胶质前体。
DOI：
10.1084/jem.20080421
发表时间：
2008-09-29
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Getts DR;Terry RL;Getts MT;Müller M;Rana S;Shrestha B;Radford J;Van Rooijen N;Campbell IL;King NJ
通讯作者：
King NJ
影响因子：
8.8
作者：
DeFalco T;Potter SJ;Williams AV;Waller B;Kan MJ;Capel B
通讯作者：
Capel B
影响因子：
12.3
作者：
Gentleman RC;Carey VJ;Bates DM;Bolstad B;Dettling M;Dudoit S;Ellis B;Gautier L;Ge Y;Gentry J;Hornik K;Hothorn T;Huber W;Iacus S;Irizarry R;Leisch F;Li C;Maechler M;Rossini AJ;Sawitzki G;Smith C;Smyth G;Tierney L;Yang JY;Zhang J
通讯作者：
Zhang J