乳腺肿瘤相关巨噬细胞分泌CCL18诱导化疗耐药相关成纤维细胞亚群活化的机制研究

Chemo-resistance is one of the major causes of death in breast cancer patients. The tumor microenvironment plays an important role in cancer development. However, the complicated regulatory network asks for further explored. Tumor-associated fibroblasts (CAFs) are the most important stromal cells in the tumor environment. However, the correlation between the density of CAFs and the prognosis of cancer patients is controversial, suggesting that tumor-associated fibroblasts are significantly heterogeneous. Our previous study found that a special subset of tumor-associated fibroblasts (CD10+GPR77+ CAFs) in breast cancer could mediate chemoresistance of breast cancer. However, their origin and the activation mechanisms are still unclear. This project was intended to focus on the scientific issue that "CCL18 secreted by tumor associated macrophages induces the activation of normal breast fibroblasts to a chemoresistance-inducing phenotype". We will try to explore mechanism of the interaction between these two important tumor stromal cells and their influence on chemoresistance by employing the neoadjuvant chemotherapy model and the humanized mouse model to simulate the real human tumor microenvironment. And figure out the possibility of finding new therapeutic target within the interaction of stromal cells in tumor microenvironment.

化疗耐药是乳腺癌患者的主要死亡原因之一，肿瘤微环境与恶性肿瘤的发生发展关系密切，然而具体的调控网络仍有待深入挖掘。肿瘤相关成纤维细胞是肿瘤间质中重要的间质细胞成分之一，但是其浸润程度与肿瘤患者预后的相关性存在很大争议，提示肿瘤相关成纤维细胞具有显著异质性。申请人前期研究发现乳腺癌中存在一个特殊亚群的肿瘤相关成纤维细胞（CD10+GPR77+ CAFs）可以介导乳腺癌化疗耐药，然而其来源和活化启动机制尚不清楚。本研究拟围绕“乳腺癌肿瘤相关巨噬细胞通过分泌CCL18诱导乳腺正常成纤维细胞活化为促化疗耐药表型的特殊肿瘤相关成纤维细胞亚群”这一科学问题，从乳腺癌术前辅助化疗模型出发，借助人源化荷瘤小鼠模型等模拟人真实肿瘤微环境，深入探索乳腺癌微环境中两个重要的间质细胞成分的相互作用机制及其对乳腺癌化疗耐药的作用。探讨针对肿瘤微环境间质细胞互动的节点分子寻找肿瘤诊治新靶标的可能。

CD10,GPR77双阳性的肿瘤相关成纤维细胞（CD10+GPR77+CAFs）是乳腺癌肿瘤微环境中介导乳腺癌化疗耐受的特异成纤维细胞亚群。然而，其确切的来源和活化启动机制此前仍然未明确。本项目通过借助乳腺癌术前新辅助化疗模型，分析证实了乳腺癌中CCL18阳性肿瘤相关巨噬细胞（TAMs）浸润的程度与肿瘤干细胞的富集、患者的化疗耐受性以及化疗耐受相关成纤维细胞亚群CD10+GPR77+CAFs的富集程度呈显著正相关性；并通过深入的机制研究和一系列的体内外实验证实肿瘤相关巨噬细胞可通过分泌CCL18作用于间质固有的成纤维细胞，诱导其向化疗耐受诱导表型（CD10+GPR77+CAFs）分化，而通过中和抗体阻断TAMs分泌的CCL18或着沉默成纤维细胞中CCL18受体PITPNM3的表达能够显著抑制肿瘤相关巨噬细胞对成纤维细胞促肿瘤耐药表型的诱导作用。研究从肿瘤微环境中间质细胞互动的角度入手创新性地发现了间质炎症细胞与固有间质细胞相互作用调控肿瘤化疗耐受性的新模式，深入阐明了TAMs调控特殊亚群CAFs的活化机制，对深化对肿瘤微环境复杂调控网络的认识具有重要理论补充意义，并有望为靶向肿瘤微环境的治疗策略提供新思路和新依据。