c-Met Mediated Cytokine Network Promotes Brain Metastasis of Breast Cancer by Remodeling Neutrophil Activities.
c-Met Mediated Cytokine Network Promotes Brain Metastasis of Breast Cancer by Remodeling Neutrophil Activities.
复制标题
作者：
已知多种非癌细胞参与脑转移，并且对中性粒细胞在该事件中的作用知之甚少。我们的目的是了解肿瘤浸润的中性粒细胞如何促进乳腺癌脑转移以及肿瘤细胞如何影响中性粒细胞的特性。利用基于患者的分析以及我们独特的动物模型，我们发现几种c-Met介导的炎性细胞因子，包括CXCL 1/2和G/GM-CSF，对转移性病变中的中性粒细胞募集和活性至关重要。反过来，由这些因子激活的中性粒细胞分泌高水平的脂质运载蛋白2（LCN 2），这反过来又增强了肿瘤细胞的干细胞性。我们的研究揭示了中性粒细胞和脑转移瘤细胞之间的新型相互作用，这可能为治疗脑转移瘤提供新的见解。脑是乳腺癌患者中最常见的转移部位之一，尤其是那些Her 2阳性或三阴性肿瘤患者。脑微环境被认为是免疫特权的，并且脑微环境中的免疫细胞如何促进脑转移的确切机制仍然难以捉摸。在本研究中，我们发现中性粒细胞在转移部位被c-Met高脑转移细胞募集和影响，并且在动物模型中，中性粒细胞的耗竭显著抑制脑转移。c-Met在肿瘤细胞中的过表达增强了一组细胞因子的分泌，包括CXCL 1/2、G-CSF和GM-CSF，其在中性粒细胞吸引、粒细胞生成和稳态中起关键作用。同时，我们的转录组学分析表明，来自c-Met高细胞的条件培养基显著诱导中性粒细胞分泌脂质运载蛋白2（LCN 2），这反过来又促进癌症干细胞的自我更新。我们的研究揭示了先天免疫细胞和肿瘤细胞之间的串扰如何促进脑中肿瘤进展的分子和致病机制，这为治疗脑转移提供了新的治疗靶点。
Multiple non-cancerous cells are known to be involved in brain metastasis, and the roles of neutrophils during this event are poorly understood. We aim to understand how tumor-infiltrated neutrophils promote breast cancer brain metastasis and how tumor cells affect the properties of neutrophils. Utilizing patient-based analyses together with our unique animal models, we discovered that several c-Met mediated inflammatory cytokines, including CXCL1/2 and G/GM-CSF, are critical to the neutrophil recruitment and activity in the metastatic lesions. In return, neutrophils activated by those factors secrete a high level of lipocalin 2 (LCN2), which in turn enhances the stemness of tumor cells. Our study revealed novel interactions between neutrophils and brain metastatic cells, which may offer new insight into treating brain metastasis. The brain is one of the most common metastatic sites among breast cancer patients, especially in those who have Her2-positive or triple-negative tumors. The brain microenvironment has been considered immune privileged, and the exact mechanisms of how immune cells in the brain microenvironment contribute to brain metastasis remain elusive. In this study, we found that neutrophils are recruited and influenced by c-Met high brain metastatic cells in the metastatic sites, and depletion of neutrophils significantly suppressed brain metastasis in animal models. Overexpression of c-Met in tumor cells enhances the secretion of a group of cytokines, including CXCL1/2, G-CSF, and GM-CSF, which play critical roles in neutrophil attraction, granulopoiesis, and homeostasis. Meanwhile, our transcriptomic analysis demonstrated that conditioned media from c-Met high cells significantly induced the secretion of lipocalin 2 (LCN2) from neutrophils, which in turn promotes the self-renewal of cancer stem cells. Our study unveiled the molecular and pathogenic mechanisms of how crosstalk between innate immune cells and tumor cells facilitates tumor progression in the brain, which provides novel therapeutic targets for treating brain metastasis.
登录
查看更多内容
影响因子：
8
作者：
Buschhaus, Johanna M.;Rajendran, Shrila;Humphries, Brock A.;Cutter, Alyssa C.;Muniz, Ayse J.;Ciavattone, Nicholas G.;Buschhaus, Alexander M.;Caneque, Tatiana;Nwosu, Zeribe C.;Sahoo, Debashis;Bevoor, Avinash S.;Shah, Yatrik M.;Lyssiotis, Costas A.;Ghosh, Pradipta;Wicha, Max S.;Rodriguez, Raphael;Luker, Gary D.
通讯作者：
Luker, Gary D.
影响因子：
50.3
作者：
Granot Z;Henke E;Comen EA;King TA;Norton L;Benezra R
通讯作者：
Benezra R
影响因子：
64.8
作者：
Finisguerra V;Di Conza G;Di Matteo M;Serneels J;Costa S;Thompson AA;Wauters E;Walmsley S;Prenen H;Granot Z;Casazza A;Mazzone M
通讯作者：
Mazzone M
术后腹腔中的低密度中性粒细胞（LDN）通过产生中性粒细胞胞外捕获物（NET）来帮助腹膜复发。
影响因子：
4.6
作者：
Kanamaru R;Ohzawa H;Miyato H;Matsumoto S;Haruta H;Kurashina K;Saito S;Hosoya Y;Yamaguchi H;Yamashita H;Seto Y;Lefor AK;Sata N;Kitayama J
通讯作者：
Kitayama J
影响因子：
30.5
作者：
Li P;Lu M;Shi J;Gong Z;Hua L;Li Q;Lim B;Zhang XH;Chen X;Li S;Shultz LD;Ren G
通讯作者：
Ren G