Daam1募集Fascin1调控乳腺癌细胞伪足形成和趋触运动的机制研究

Breast cancer, characterized by a high malignant and metastatic potential, principally affects female health. Metastasis of breast cancer is a major reason threatening the patients health and even survival. The microenvironment in regions where tumors are forming and expanding is characterized by progressive loss of specialized or differentiated cellular functions, disorderly molecular signals, degeneration of microscopical organ structure. Our recent novel findings indicated that Daam1 and Fascin1 regulated the migration of breast cancer cells. The pseudopodia extension and haptotaxis of breast cancer cells are the first step of cancer cell migration, subsequently leading to tumor metastasis. However, the mechanisms of pseudopodia extension and haptotaxis of breast cancer cells are not well understood. The priorities of our work are to elucidate: (1) Whether Daam1 regulates collagen-mediated microfilament assemble, pseudopodia extension, haptotaxis of breast cancer cells, and breast cancer metastasis? (2) Whether Daam1 recruits Fascin1 to regulate collagen-mediated microfilament assemble, pseudopodia extension, haptotaxis of breast cancer cells, and breast cancer metastasis? Our research would provide better understanding of the molecular mechanisms involved in breast cancer metastasis.

乳腺癌是当今世界女性最常见的恶性肿瘤之一，其高转移性是威胁患者健康乃至生命的主要原因。乳腺癌的转移受到乳腺肿瘤微环境的影响和调节，肿瘤微环境是当前肿瘤研究的前沿和热点。乳腺癌细胞的伪足形成是其响应肿瘤微环境、促使乳腺癌细胞趋触运动的始动步骤和关键环节，然而我们不清楚Daam1和Fascin1是否参与乳腺癌细胞伪足形成和趋触运动的调节，进而调控乳腺癌的转移。本工作在以往研究结果的基础上致力于阐明：（1）Daam1是否调控胶原蛋白诱导的微丝组装、乳腺癌细胞伪足形成、趋触运动和乳腺癌转移？（2）Daam1是否通过募集Fascin1至趋触运动的前端，进而调控胶原蛋白诱导的微丝组装、乳腺癌细胞伪足形成、趋触运动和乳腺癌转移？我们希望本研究目标的完成会使人们对乳腺癌细胞的伪足形成和趋触运动，进而实现乳腺癌转移的机理有更深入的认识。

乳腺癌是当今世界女性最常见的恶性肿瘤之一，其高转移性是威胁患者健康乃至生命的主要原因。乳腺癌的转移受到乳腺肿瘤微环境的影响和调节，乳腺癌细胞的伪足形成是其响应肿瘤微环境、促使乳腺癌细胞趋触运动的始动步骤和关键环节。本项目研究发现并证明：Integrin αvβ3/DAAM1信号通路调控乳腺癌细胞胶原蛋白诱导的侵入伪足形成和细胞定向迁移；miR-613靶向Daam1调控三阴性乳腺癌的浸润与迁移；低剂量山奈酚下调RhoA和Rac1活性并抑制三阴性乳腺癌细胞迁移和侵袭；miR-3622b-5p和miR-1296-5p对HER2+乳腺癌具有抑癌作用；SMAR1通过T-bet/PD-1轴促进三阴性乳腺癌的免疫逃逸；Ezrin和细胞骨架相关蛋白Cortactin相互作用促进乳腺癌细胞的上皮间质转化；血浆CCL5加剧晚期乳腺癌的表柔红霉素耐药。本研究的完成会使人们对乳腺癌细胞的伪足形成和趋触运动，进而实现乳腺癌转移的机理有更深入的认识。