STAT5 is activated in macrophages by breast cancer cell-derived factors and regulates macrophage function in the tumor microenvironment.
STAT5 is activated in macrophages by breast cancer cell-derived factors and regulates macrophage function in the tumor microenvironment.
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DOI：
10.1186/s13058-021-01481-0
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发表时间：
2021-11-07
期刊：
影响因子：
--
通讯作者：
Schwertfeger KL
中科院分区：
文献类型：
--
作者：
Jesser EA;Brady NJ;Huggins DN;Witschen PM;O'Connor CH;Schwertfeger KL
在乳腺癌中，肿瘤细胞与周围基质内的细胞（例如巨噬细胞）之间复杂的相互作用对于肿瘤生长、进展和治疗反应至关重要。最近的研究强调了与肿瘤促进和肿瘤抑制表型相关的巨噬细胞的复杂性质和异质群体。定义驱动巨噬细胞功能的途径对于理解巨噬细胞在肿瘤微环境中的复杂表型非常重要。信号转导子和转录激活子 (STAT) 转录因子，例如 STAT5，是免疫细胞功能的关键调节因子。本文描述的研究调查了 STAT5 对乳腺癌肿瘤相关巨噬细胞功能的功能贡献。初步研究使用一组人类乳腺癌和小鼠乳腺肿瘤细胞系进行，以确定肿瘤细胞衍生因子诱导巨噬细胞中 STAT5 激活的能力。进一步的研究使用这些模型来识别激活巨噬细胞中 STAT5 的可溶性因子。为了描述 STAT5 对巨噬细胞功能的特异性贡献，使用骨髓 STAT5 缺失的条件模型进行体外、RNA 测序和体内研究。使用体外共培养迁移测定和体内肿瘤细胞-巨噬细胞共注射模型评估巨噬细胞中STAT5缺失对肿瘤细胞迁移和转移的影响。我们在此证明 STAT5 在巨噬细胞中被肿瘤细胞衍生因子强力激活，并且 GM-CSF 是刺激该途径的关键细胞因子。 RNA-seq研究分析表明，STAT5促进巨噬细胞中免疫刺激基因的表达，巨噬细胞中STAT5的缺失会导致组织重塑因子表达增加。最后，我们证明巨噬细胞中STAT5的缺失可促进体外肿瘤细胞迁移和体内乳腺肿瘤转移。乳腺癌细胞产生可溶性因子，例如 GM-CSF，激活巨噬细胞中的 STAT5 通路并驱动炎症因子的表达。骨髓细胞中 STAT5 的缺失会增强转移，这表明肿瘤相关巨噬细胞中 STAT5 的激活可以防止肿瘤进展。了解在肿瘤微环境中驱动巨噬细胞功能的机制将最终导致抑制肿瘤促进功能同时增强其抗肿瘤功能的新方法。在线版本包含可在 10.1186/s13058-021-01481-0 获取的补充材料。
In breast cancer, complex interactions between tumor cells and cells within the surrounding stroma, such as macrophages, are critical for tumor growth, progression, and therapeutic response. Recent studies have highlighted the complex nature and heterogeneous populations of macrophages associated with both tumor-promoting and tumor-inhibiting phenotypes. Defining the pathways that drive macrophage function is important for understanding their complex phenotypes within the tumor microenvironment. Signal transducer and activator of transcription (STAT) transcription factors, such as STAT5, are key regulators of immune cell function. The studies described here investigate the functional contributions of STAT5 to tumor-associated macrophage function in breast cancer. Initial studies were performed using a panel of human breast cancer and mouse mammary tumor cell lines to determine the ability of tumor cell-derived factors to induce STAT5 activation in macrophages. Further studies used these models to identify soluble factors that activate STAT5 in macrophages. To delineate STAT5-specific contributions to macrophage function, a conditional model of myeloid STAT5 deletion was used for in vitro, RNA-sequencing, and in vivo studies. The effects of STAT5 deletion in macrophages on tumor cell migration and metastasis were evaluated using in vitro co-culture migration assays and an in vivo tumor cell-macrophage co-injection model. We demonstrate here that STAT5 is robustly activated in macrophages by tumor cell-derived factors and that GM-CSF is a key cytokine stimulating this pathway. The analysis of RNA-seq studies reveals that STAT5 promotes expression of immune stimulatory genes in macrophages and that loss of STAT5 in macrophages results in increased expression of tissue remodeling factors. Finally, we demonstrate that loss of STAT5 in macrophages promotes tumor cell migration in vitro and mammary tumor metastasis in vivo. Breast cancer cells produce soluble factors, such as GM-CSF, that activate the STAT5 pathway in macrophages and drive expression of inflammatory factors. STAT5 deletion in myeloid cells enhances metastasis, suggesting that STAT5 activation in tumor-associated macrophages protects against tumor progression. Understanding mechanisms that drive macrophage function in the tumor microenvironment will ultimately lead to new approaches that suppress tumor-promoting functions while enhancing their anti-tumor functions. The online version contains supplementary material available at 10.1186/s13058-021-01481-0.
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影响因子：
6.2
作者：
Brenot A;Knolhoff BL;DeNardo DG;Longmore GD
通讯作者：
Longmore GD
影响因子：
5.3
作者：
Creamer, Bradley A.;Sakamoto, Kazuhito;Wagner, Kay-Uwe
通讯作者：
Wagner, Kay-Uwe
影响因子：
8
作者：
Bos, R;van Diest, PJ;Shvarts, A
通讯作者：
Shvarts, A
DOI：
10.1039/c5ib00040h
发表时间：
2015-10
期刊：
Integrative biology : quantitative biosciences from nano to macro
影响因子：
--
作者：
Acerbi I;Cassereau L;Dean I;Shi Q;Au A;Park C;Chen YY;Liphardt J;Hwang ES;Weaver VM
通讯作者：
Weaver VM
影响因子：
11.2
作者：
Bohrer LR;Chuntova P;Bade LK;Beadnell TC;Leon RP;Brady NJ;Ryu Y;Goldberg JE;Schmechel SC;Koopmeiners JS;McCarthy JB;Schwertfeger KL
通讯作者：
Schwertfeger KL