乳腺癌通过DMBT1诱导CD62L+ Kupffer细胞,促进中性粒细胞胞外陷阱形成和肝脏转移。

IF 12.5 1区 生物学 Q1 CELL BIOLOGY
Pu Tian, Qiuyao Wu, Dasa He, Wenjing Zhao, Lichao Luo, Zhenchang Jia, Wenqian Luo, Xianzhe Lv, Yanan Liu, Yuan Wang, Qian Wang, Peiyuan Zhang, Yajun Liang, Qifeng Yang, Guohong Hu
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引用次数: 0

摘要

肝脏是乳腺癌转移的主要靶器官,但乳腺癌在肝脏定殖的调控机制仍不清楚。已知中性粒细胞通过形成中性粒细胞胞外陷阱(NETs)在癌细胞的转移定植中发挥重要作用。在这里,我们展示了库普弗细胞(KCs)亚群,肝脏巨噬细胞,在介导NETs肿瘤诱导和肝脏转移中的作用和机制。与转移到其他器官和原发肿瘤的肿瘤相比,乳腺癌肝转移灶中的NETs被更丰富地激活。嗜肝肿瘤细胞通过分泌蛋白DMBT1诱导表达CD62L的KCs, CD62L+ KCs通过趋化因子CCL8激活中性粒细胞NETosis。抑制CCL8或其在中性粒细胞上的受体CCR1,会损害NETosis和转移。此外,我们发现KC膜蛋白MUC1与DMBT1结合,随后激活KC中的NF-κB信号传导,导致CCL8和CD62L表达。MUC1抑制的KCs可有效抑制肝转移。此外,一种DMBT1中和抗体被开发出来,有望抑制肿瘤- kc相互作用并治疗转移性癌症。总之,我们的工作揭示了一个KC亚群,它解释了乳腺癌细胞和NETs的肝向性,并为转移治疗提供了潜在的策略。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Breast cancer induces CD62L+ Kupffer cells via DMBT1 to promote neutrophil extracellular trap formation and liver metastasis.

The liver is a major target organ for breast cancer metastasis, while the regulatory mechanism of liver colonization by breast cancer remains largely unclear. Neutrophils are known to play important roles in metastatic colonization of cancer cells by the formation of neutrophil extracellular traps (NETs). Here we show the role and mechanism of a subpopulation of Kupffer cells (KCs), the liver resident macrophages, in mediating tumoral induction of NETs and liver metastasis. NETs are activated more abundantly in liver metastases of breast cancer, as compared to metastases to other organs and primary tumors. Liver-tropic tumor cells induce CD62L-expressing KCs by a secretory protein DMBT1, and CD62L+ KCs activate neutrophils for NETosis via the chemokine CCL8. Inhibition of CCL8 or its receptor on neutrophils, CCR1, impairs NETosis and metastasis. In addition, we identified a KC membrane protein MUC1 that binds to DMBT1 and subsequently activates NF-κB signaling in KCs, leading to CCL8 and CD62L expression. KCs with MUC1 inhibition effectively suppress liver metastasis. Furthermore, a DMBT1 neutralizing antibody was developed with the promise to inhibit tumor-KC interaction and treat metastatic cancer. In conclusion, our work reveals a KC subset that accounts for the liver tropism of breast cancer cells and NETs, and provides potential strategies in metastasis treatment.

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来源期刊
Cell Discovery
Cell Discovery Biochemistry, Genetics and Molecular Biology-Molecular Biology
CiteScore
24.20
自引率
0.60%
发文量
120
审稿时长
20 weeks
期刊介绍: Cell Discovery is a cutting-edge, open access journal published by Springer Nature in collaboration with the Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences (CAS). Our aim is to provide a dynamic and accessible platform for scientists to showcase their exceptional original research. Cell Discovery covers a wide range of topics within the fields of molecular and cell biology. We eagerly publish results of great significance and that are of broad interest to the scientific community. With an international authorship and a focus on basic life sciences, our journal is a valued member of Springer Nature's prestigious Molecular Cell Biology journals. In summary, Cell Discovery offers a fresh approach to scholarly publishing, enabling scientists from around the world to share their exceptional findings in molecular and cell biology.
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