乳腺癌细胞外泌体miR-29a通过诱导单核巨噬细胞M2型转化促进肿瘤转移的功能与机制

Lung metastasis of breast cancer is one of the major causes of death in breast cancer patients. The microenvironment of the metastatic target organs is crucially important for the colonization and growth of cancer cells. In the preliminary studies, we found high expression of miR-29a is closely related to the malignant progression of breast cancer. Our latest pilot experiments show breast cancer cell-derived exosomal miR-29a can recruit monocytes to lung and induce them to differentiate into tumor associated macrophages (TAMs), which can promote the mesenchymal-epithelial transition (MET) and proliferation of the metastatic cancer cells. This project intends to carry out in vitro and vivo experiments to connect the past and future researches. The goals of this project are: 1) To identify the molecular function and mechanism which are how exosomal miR-29a recruits monocytes to the lung and induces them into TAMs; 2) To reveal the molecular mechanism via which TAMs promote the MET and proliferation of breast cancer cells in the lung metastatic microenvironment; 3) To confirm the relationship between lung metastasis and the biometric data in peripheral blood of breast cancer patients including miR-29a level, macrophage subsets, key factors of MET regulated by the macrophages; furthermore, to access their clinical value; 4) To thoroughly illustrate the actual molecular mechanisms that exosomal miR-29a recruits and induces the differentiation of monocytes to promote the MET and colonization of metastatic breast cancer cells in lung. This project is expected to provide experimental research foundation for revealing the mechanism of breast cancer lung metastasis and exploring novel treatment targets.

乳腺癌肺转移是病人死亡的主要原因之一；肿瘤转移靶器官的微环境对癌细胞的定植和生长至关重要。我们前期发现miR-29a高表达与乳腺癌恶性进展密切相关；我们最近的预实验结果提示：乳腺癌细胞外泌体miR-29a可招募单核细胞至肺并诱导其向肿瘤相关巨噬细胞（TAM）分化；TAMs又可促进转移灶中的癌细胞发生间质-上皮转化（MET）、提高其增殖能力。本项目拟承前启后，将通过一系列体内外实验，明确外泌体miR-29a诱导单核巨噬细胞至肺、形成TAMs的分子功能与机制；解析肺转移微环境中TAMs促进乳腺癌细胞MET和生长的分子机理；确证乳腺癌病人外周血中miR-29a、巨噬细胞亚群及其调控MET关键因子的水平与肿瘤肺转移的相关性和临床价值；深入阐明外泌体miR-29a通过募集和诱导巨噬细胞分化为TAMs、促进癌细胞MET和肺内定植转移的确切分子机制，为揭示乳腺癌肺转移机理和发现抗癌新靶点提供实验研究基础

乳腺癌肺转移是病人死亡的主要原因之一；肿瘤转移靶器官的微环境对癌细胞的定植和生长至关重要。我们前期发现miR-29a高表达与乳腺癌恶性进展密切相关；我们最近的预实验结果提示：乳腺癌细胞外泌体miR-29a可招募单核细胞至肺并诱导其向肿瘤相关巨噬细胞（TAM）分化；TAMs又可促进转移灶中的癌细胞发生间质-上皮转化（MET）、提高其增殖能力。本项目拟承前启后，将通过一系列体内外实验，明确外泌体miR-29a诱导单核巨噬细胞至肺、形成TAMs的分子功能与机制；解析肺转移微环境中TAMs促进乳腺癌细胞MET和生长的分子机理；确证乳腺癌病人外周血中miR-29a、巨噬细胞亚群及其调控MET关键因子的水平与肿瘤肺转移的相关性和临床价值；深入阐明外泌体miR-29a通过募集和诱导巨噬细胞分化为TAMs、促进癌细胞MET和肺内定植转移的确切分子机制，为揭示乳腺癌肺转移机理和发现抗癌新靶点提供实验研究基础。项目构建乳腺癌及其微环境细胞来源外泌体的耐药分子图谱； 分析原发和继发耐乳腺癌临床标本的外泌体分子图谱特征；建立外泌体快速低成本获取技术； 开发针对乳腺癌化疗耐药关键分子的诊疗新策略；实施外泌体耐药分子图谱的临床转化应用。