TGFβ2促发内质网应激在巨噬细胞参与乳腺癌耐药和转移中的作用及机制

The drug-resistance and metastasis are the major obstacles for the successful breast cancer treatment clinically. We previously found that macrophages recruitment and polarization related cytokines TGFβ2, CCL-2 and CSF-1 expression were up-regulated in multidrug-resistant breast cancer (MR-BC) cells with mesenchymal-like phenotype, whereas, the interferences in their signals did not reverse the biological behaviors. Moreover, our findings suggest that TGFβ2 maybe promote breast cancer progression via educating macrophages to tumor-associated macrophages (TAMs). In the present program, we will first confirm the effects of TAMs educated by drug-resistant BC cells in vitro and in vivo on growth, drug resistance and metastasis of BC cells. Then, we will explore the roles of TGFβ2 triggered endoplasmic reticulum stress (ERS) via mTORC1 signal in macrophages in the process of drug-resistant BC cells educating macrophages to TAMs. The third, we will investigate the effects of IRE1α-XBP1signal mediated ERS in the process of TAMs promoting breast cancer progression in vitro and in vivo. Through these researches, we will reveal the roles and mechanisms of the cross-talk between drug-resistant BC cells and Macrophages, which will provide new clues for the mechanisms study for drug-resistance and metastasis, and the development of new strategies to reverse drug-resistance and metastasis in breast cancer.

耐药和转移是限制乳腺癌疗效提高的关键原因，我们发现与巨噬细胞募集并极化成肿瘤相关巨噬细胞（TAMs）相关的TGFβ2、CCL-2及CSF-1等在具有间质表型的乳腺癌耐药细胞中表达上调，但干预TGFβ2等信号并不能有效逆转耐药细胞本身的生物学行为，且体内外实验结果提示耐药细胞可能通过TGFβ2教化巨噬细胞而促进乳腺癌进展。本项目拟先从体内实验进一步观察由乳腺癌耐药细胞在体内外教化而来的TAMs对乳腺癌生长、耐药及转移的影响；其次阐述TGFβ2通过活化巨噬细胞中mTORC1而促发的内质网应激（ERS）在耐药细胞教化巨噬细胞向TAMs极化中的作用；再者从体内外实验及临床组织分析IRE1α-XBP1介导的ERS在TAMs促进乳腺癌生长、耐药及转移中的作用。本项目的完成将为揭示耐药细胞与巨噬细胞交互作用的机制及其效应，为探讨乳腺癌耐药和转移的新分子机制及开发新干预策略提供新思路。

耐药和转移是限制乳腺癌疗效提高的关键原因，临床观察和实验研究表明肿瘤耐药与肿瘤转移密切相关，肿瘤微环境中肿瘤相关细胞(TAMs)浸润与患者预后不良密切相关，但相互之间的内在联系机制仍有待阐明。本研究发现乳腺癌多药耐药细胞呈现EMT（上皮-间质转化）表型，体内外模型中耐药细胞可募集并教化巨噬细胞向TAMs表型极化且促癌因子表达和分泌增加，耐药细胞可促进亲本敏感细胞生长并诱导系统性耐药，清除巨噬细胞则抑制耐药细胞对亲本细胞耐药的诱导作用。机制上，耐药细胞通过分泌CSF1和TGFβ2维持巨噬细胞生长并教化成TAMs表型，TGFβ2通过活化Smads转录上调巨噬细胞中Raptor表达，活化mTOR信号，诱发XBP1依赖性内质网应激（ERS），抑制mTOR活性或ERS则消除耐药细胞诱导巨噬细胞向TAMs表型极化。反馈性地，经耐药细胞教化的TAMs可诱导亲本细胞发生EMT，体内外促进亲本细胞侵袭、转移、生长和耐药。在临床乳腺癌组织样本上，化疗耐药乳腺癌组织中TGFβ2表达和TAMs浸润高于化疗敏感乳腺癌组织，TGFβ2表达和TAMs浸润与乳腺癌患者预后呈负相关。本研究从肿瘤微环境的角度探索乳腺癌耐药细胞与巨噬细胞的交互作用及生物学功能，为乳腺癌耐药和转移的机制研究提供新线索，为开发监测乳腺癌治疗反应性、逆转乳腺癌耐药及预防乳腺癌化疗过程中发生转移的新诊治策略提供新思路。.在本研究执行期间，标注本研究资助，申请人以第一或通讯作者发表SCI论文7篇，申获广州市珠江科技新星项目和“广东特支计划”科技创新青年拔尖人才项目，申请并被受理专利1项，培养毕业硕士研究生2名。