MD-2特异性识别游离脂肪酸触发NETosis，肥胖相关乳腺癌肺转移的新机制？

肥胖与乳腺癌肺转移密切相关，嗜中性粒细胞（PMN）在前转移灶内广泛浸润是肥胖促进乳癌肺转移的早期事件，其活化形式及作用机理仍未阐明。我们发现：高脂膳食诱导肥胖进程中，中性粒细胞胞外诱捕网（NETs）显著沉积于小鼠肺毛细血管内，靶向清除肺内NETs能有效遏制乳腺癌肺转移，提示NETosis可能参与肿瘤进展过程；针对不同表型PMN筛查发现，具有MD-2标志的PMN是响应游离脂肪酸形成NETs的主体。据此，我们推测MD-2是肥胖诱导NETosis的关键调控受体蛋白，靶向抑制MD-2有望从源头阻遏肥胖相关乳癌肺转移。本课题拟结合病例资料，进一步明确NETosis在肥胖相关乳腺癌肺转移过程中的作用和地位。并系统地应用体内外转移模型，解析MD-2依赖的NETosis触发因素、活化途径及调控网络，揭示它对肿瘤细胞定植和增殖的影响，为今后创新型开展肥胖相关性乳腺癌肺转移的防治工作提供新的思路和实验依据。

Obesity is linked with the development of distant metastasis, especially lung metastasis. Comprehensive infiltration of neutrophils in pre-metastatic niche is an early hallmark of lung metastasis in obesity-related breast cancer, yet the underlying mechanism of their pro-metastatic activation remains largely unexplored. NETosis, initially identified as a fundamental host innate immune defense against pathogens, have been recently shown to facilitates metastatic disease progression under septic conditions. NETs expelled from neutrophil function to sequester circulating tumor cells (CTCs), reprogram the bioenergetics of cancer cells, and thus increase metastatic spread in distant organs. Our laboratory has recently demonstrated the novel finding that widespread deposition of NETs within lung microvasculature of high-fat diet-induced obesity mouse, accompanied by extended release of circulating myeloperoxidase (MPO)-DNA complexes levels, another specific marker of NETosis. Disruption of existing NETs by nucleic-acid scavengers ameliorates metastatic tumor cell colonization and obesity-related breast cancer lung metastasis. Most importantly, we discovered that a subset of (MD-2+) neutrophils from the bone marrow undergoes NETosis in response to free fatty acids (FFA) treatment. This discovery makes the conceptual argument that MD-2, the principal regulatory molecule for innate immune recognition, confers FFA responsiveness in host neutrophils and can signal to activate the TLR4/MyD88/PAD4, initiate NETosis and shape the pre-metastatic niche, and eventually leading to the occurrence of lung cancer metastasis in breast cancer. The proposed study will use an integrative systems approach to understand the potential triggers and specific molecular mechanisms of NETosis in the setting of the obesity-related inflammation. The findings will be corroborated by an extensive clinical biobank that contains a large collection of breast cancer lung metastases. Our study will identify the molecular determinants of pro-metastatic activation of neutrophil in pre-metastatic niche, and provide new information for devising a novel therapeutic modality for obesity-related breast cancer lung metastasis.