A Novel ACKR2-Dependent Role of Fibroblast-Derived CXCL14 in Epithelial-to-Mesenchymal Transition and Metastasis of Breast Cancer
A Novel ACKR2-Dependent Role of Fibroblast-Derived CXCL14 in Epithelial-to-Mesenchymal Transition and Metastasis of Breast Cancer
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DOI：
10.1158/1078-0432.ccr-18-1294
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发表时间：
2019-06-15
影响因子：
11.5
通讯作者：
Ostman, Arne
中科院分区：
文献类型：
--
作者：
Sjoberg, Elin;Meyrath, Max;Ostman, Arne
目的：表达孤儿趋化因子CXCL14的成纤维细胞先前已被证明与乳腺癌预后不良和促进癌症生长有关。本研究探讨了间质CXCL14低生存率相关性的机制。实验设计：在体外和体内模型中，与过表达CXCL14的成纤维细胞一起研究肿瘤细胞上皮细胞向间质转化（EMT）、侵袭和转移。CXCL14受体鉴定的方法包括功能丧失研究，然后是分子和功能终点。在公开的基因表达数据集中进一步探讨了临床相关性。结果：CXCL14成纤维细胞在乳腺癌细胞和异种移植模型中刺激乳腺癌EMT、迁移和侵袭。此外，由CXCL14成纤维细胞引发的肿瘤细胞在尾静脉注射后显示出增强的肺定植。通过功能缺失实验，发现非典型g蛋白偶联受体ACKR2介导cxcl14刺激反应。ACKR2或cxcl14诱导的NOS1下调会减弱促emt和迁移能力。在基因表达数据集中，CXCL14/ACKR2表达与EMT和生存率相关。结论：总的来说，这些发现表明自分泌成纤维细胞CXCL14/ACKR2通路是EMT、肿瘤细胞侵袭和转移的临床相关刺激因子。该研究还确定了ACKR2作为CXCL14功能的新介质，从而确定了具有药物靶标潜力的途径。
Purpose: Fibroblasts expressing the orphan chemokine CXCL14 have been previously shown to associate with poor breast cancer prognosis and promote cancer growth. This study explores the mechanism underlying the poor survival associations of stromal CXCL14.Experimental Design: Tumor cell epithelial-to-mesenchymal transition (EMT), invasion, and metastasis were studied in in vitro and in vivo models together with fibroblasts overexpressing CXCL14. An approach for CXCL14 receptor identification included loss-of-function studies followed by molecular and functional endpoints. The clinical relevance was further explored in publicly available gene expression datasets.Results: CXCL14 fibroblasts stimulated breast cancer EMT, migration, and invasion in breast cancer cells and in a xenograft model. Furthermore, tumor cells primed by CXCL14 fibroblasts displayed enhanced lung colonization after tailvein injection. By loss-of function experiments, the atypical G-protein-coupled receptor ACKR2 was identified to mediate CXCL14-stimulated responses. Downregulation of ACKR2, or CXCL14-induced NOS1, attenuated the pro-EMT and migratory capacity. CXCL14/ACKR2 expression correlated with EMT and survival in gene expression datasets.Conclusions: Collectively, the findings imply an autocrine fibroblast CXCL14/ACKR2 pathway as a clinically relevant stimulator of EMT, tumor cell invasion, and metastasis. The study also identifies ACKR2 as a novel mediator for CXCL14 function and thereby defines a pathway with drug target potential.