Reprogramming of tumor-associated macrophages by targeting β-catenin/FOSL2/ARID5A signaling: A potential treatment of lung cancer
Reprogramming of tumor-associated macrophages by targeting β-catenin/FOSL2/ARID5A signaling: A potential treatment of lung cancer
复制标题
通过靶向β-连环蛋白/FOSL2/ARID5A信号通路对肿瘤相关巨噬细胞进行重编程：一种潜在的肺癌治疗方法
DOI：
10.1126/sciadv.aaz6105
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发表时间：
2020-06-01
期刊：
影响因子：
13.6
通讯作者：
Savai, Rajkumar
中科院分区：
文献类型：
--
作者：
Sarode, Poonam;Zheng, Xiang;Savai, Rajkumar
肿瘤相关巨噬细胞（TAM）通过诱导免疫抑制影响肺肿瘤的发展。从人肺肿瘤组织中分离的TAM的转录组分析揭示了Wnt/β-连环蛋白途径的上调。这些发现在新开发的体外“训练”TAM模型中重现。在体外和各种体内模型中，β-连环蛋白的药理学和巨噬细胞特异性基因消融将M2样TAM重编程为M1样TAM，这与原发性和转移性肺肿瘤生长的抑制有关。对潜在信号事件的深入分析揭示，β-连环蛋白介导的FOS-like抗原2（FOSL 2）的转录激活和AT富集相互作用结构域5A（ARID 5A）的抑制驱动基因调控开关从M1样TAM到M2样TAM。此外，我们发现β-catenin和FOSL 2的高表达与肺癌患者的不良预后相关。总之，β-连环蛋白驱动肺肿瘤微环境中的转录开关，从而促进肿瘤进展和转移。
Tumor-associated macrophages (TAMs) influence lung tumor development by inducing immunosuppression. Transcriptome analysis of TAMs isolated from human lung tumor tissues revealed an up-regulation of the Wnt/beta-catenin pathway. These findings were reproduced in a newly developed in vitro "trained" TAM model. Pharmacological and macrophage-specific genetic ablation of beta-catenin reprogrammed M2-like TAMs to M1-like TAMs both in vitro and in various in vivo models, which was linked with the suppression of primary and metastatic lung tumor growth. An in-depth analysis of the underlying signaling events revealed that beta-catenin-mediated transcriptional activation of FOS-like antigen 2 (FOSL2) and repression of the AT-rich interaction domain 5A (ARID5A) drive gene regulatory switch from M1-like TAMs to M2-like TAMs. Moreover, we found that high expressions of beta-catenin and FOSL2 correlated with poor prognosis in patients with lung cancer. In conclusion, beta-catenin drives a transcriptional switch in the lung tumor microenvironment, thereby promoting tumor progression and metastasis.