CD40信号通路在乳腺癌转移中的调控及其靶向治疗

Recent studies support the concept that Fra1 plays an important role in the epithelial-to-mesenchymal transition (EMT) and metastasis in many types of solid tumors. The applicant has been engaged in research on tumor and cancer stem cells for many years and devoted to the exploration of novel therapeutic targets and methods for tumor. Our previous work demonstrated the regulatory effect of CD40 signaling on the transcription of Fra1 and SOX2 as well as on the stemness property in breast cancers through the high-throughput siRNA screening method. Based on previous work, we plan to apply multiple biological technologies and methods, including the in vitro experiments, CD40 ligand knock-out mice and tumor-bearing animal models etc. to perform the following experiments: 1) to verify the correlation between CD40 signaling and metastasis in breast tumor; to test transcriptional regulation effect of CD40 signal pathway on Fra1 and to further elucidate the underlying mechanism; 2) to test the function of Fra1 in mediating metastasis-promotion effect of CD40 signaling; 3) to screening and verify the novel small inhibitors that targeting the interaction between CD40 and CD40 ligand to inhibit the metastasis of breast tumor cells. This study will help us to explore more leading effective therapeutic targets and methods for breast cancer.

目前的研究普遍认为转录因子Fra1在多种实体瘤的上皮向间充质转化及转移中起到重要作用。申请者长期从事肿瘤及肿瘤干细胞的研究，并积极的探讨新的肿瘤治疗靶点及治疗方法。我们前期通过膜受体基因siRNA文库筛查的方法发现CD40信号通路可能调控乳腺癌中Fra1的表达，并调控肿瘤细胞干性及干性基因SOX2的表达。本课题拟在前期研究工作的基础上，通过体外实验、CD40配体敲除小鼠等多种成熟的转基因老鼠及荷瘤动物模型等方法完成以下研究：1）明确肿瘤细胞中CD40信号通路与乳腺癌转移的关系及对Fra1的转录调控作用及其调控机理；2）验证Fra1在介导CD40信号促肿瘤细胞转移中的作用；3）筛选靶向CD40与CD40配体相互作用的新型小分子化合物以阻断肿瘤细胞转移。本研究将为探索更有效的乳腺癌治疗靶点与方法提供前沿性理论探讨。

本课题组在四年的研究工作中按照既定的研究计划执行，较好的达到了预期目标，完成了以下工作：1）通过体内外实验证明CD40能够有效调控Fra1的表达，进一步探讨肿瘤细胞中Fra1在介导CD40促上皮向间充质转化(EMT)及肿瘤转移的作用；2）明确了CD40信号通路对Fra1调控的分子机理，明确CD40下游分子c-Jun,JunB结合到Fra1的转录启动子附近区域以促进Fra1的表达；3）通过电脑虚拟筛选及体外筛选、体外及动物体内实验验证的方法，发现调控CD40及CD40L相互作用的新型小分子化合物；4）发现了1种新型CD40抑制剂。通过体内外实验明确筛选出的小分子化合物能够抑制CD40的下游信号通路并进一步明确该CD40小分子抑制剂及协同剂即BACH1抑制剂联合应用能够增强其抗乳腺癌细胞的转移作用。本研究为制定新型的乳腺癌特别是基底样（basal-like）乳腺癌治疗方案提供了有意义的实验室前期探讨；5）已发表SCI论文3篇，其中2篇论文影响因子大于10分；6）已培养5名硕士研究生及2名博士研究生毕业。