DLK2在basal-like乳腺癌转移中的作用与机制研究

With the more potential in metastasis, chemoresistance and recurrene, basal-like breast cancer is hard to be treated. Because of the lack of effective therapeutic target molecules, targeted immunotherapy is limited in the treatment of basal like breast cancer. To search and study the potential targeted molecules mediating high metastasis in the basal-like breast cancer, the applicant adopted the cross-species expression profiling strategy and found that the expression of DLK2 highly expressed in the basal-like breast cancer cell lines. In vivo and in vitro experiments found that DLK2 could promote metastasis of breast cancer cells. Furtherly the role of DLK2 in chemo-resistance, EMT and stem cell maintenance in breast cancer cells will also be determined in this project. The key downstream genes of DLK2 and the metastasis-related critical phosphorylation sites will be discovered in this project. This study can reveal the functions and mechanisms of a potential new metastasis-associated gene, and will provide the new potential therapeutic target for the clinical treatment of the basal-like breast cancer.

Basal-like乳腺癌具有转移能力高、耐药性强和易复发等特点而成为乳腺癌治疗中的一大难题。有效治疗靶标分子的缺乏限制了免疫靶向治疗在Basal-like乳腺癌治疗中的应用。申请人立足于寻找并研究basal-like乳腺癌中介导高转移潜能同时又能作为免疫靶向治疗中的靶标分子，采用交叉物种表达谱策略发现膜蛋白DLK2在basal-like乳腺癌细胞系中高表达，体外和动物实验发现DLK2可以促进乳腺癌细胞系的转移。基于此发现，本项目拟进一步探明DLK2在basal-like乳腺癌细胞耐药、EMT以及干细胞维持中的作用，同时寻找并研究介导转移和耐药的关键下游调控基因和关键磷酸化位点以初步探明其分子机制。本研究可以揭示一个潜在的新的转移相关分子DLK2的功能和转移促进机制，为进一步临床中basal-like乳腺癌的免疫靶向治疗打下基础。

Basal-like乳腺癌具有转移能力高、耐药性强和易复发等特点而成为乳腺癌治疗中的一大难题。有效治疗靶标分子的缺乏限制了免疫靶向治疗在Basal-like乳腺癌治疗中的应用。本项目发现DLK2（又称EGFL9）在basal-like乳腺癌细胞系及肿瘤组织中高表达，并和肿瘤转移明显相关。在功能上，DLK2对促进癌细胞迁移、侵袭和远处转移是必要的和充分的。在机制上，我们证明DLK2结合cMET，激活cMET介导的下游信号。DLK2和cMET共同定位于细胞膜和线粒体内。我们进一步确定DLK2和细胞色素C氧化酶（COX）组装因子COA3之间的相互作用。因此，DLK2调节COX活性，调节细胞代谢，促进Warburg样的代谢表型。最后，我们证明联合药物抑制cMET和糖酵解逆转DLK2驱动的干细胞样特征。本研究较全面地研究了DLK2的功能和转移促进机制，为进一步临床中basal-like乳腺癌的免疫靶向治疗打下基础。