肺腺癌通过BCAR1生成高侵袭性循环肿瘤细胞及免疫逃避的研究

肺腺癌(LAC)转移存在两个关键环节：通过上皮间质转化(EMT)生成间质型循环肿瘤细胞（M-CTCs）逃避失巢凋亡；活化血小板使M-CTCs逃避NK细胞杀伤。我们发现LAC中BCAR1高表达预后差；癌组织及外周血BCAR1高表达分别与M-CTCs增多及NK失活密切相关；BCAR1\Crk复合物激活p38MAPK诱发EMT及活化血小板。我们拟通过临床观察、细胞及动物等多层面研究证实如下假设：“BCAR1\Crk\p38MAPK信号轴诱发EMT及活化血小板，从而催生M-CTCs及促使免疫逃避”。我们已获得BCAR1单抗可阻断BCAR1\Crk复合物形成;在此基础上拟通过细胞内抗体同时抑制癌细胞及血小板中BCAR1信号通路，从而预防M-CTCs形成及免疫逃避。本项目将阐明LAC复发转移机制,并有重要临床价值：LAC患者应检测癌组织及监测外周血BCAR1表达，BCAR1胞内抗体有望预防肿瘤转移。

There are two critical steps in the metastasis of lung adenocarcinoma(LAC): ① In order to evade anoikis, LAC will induce epithelial-mesenchymal transition (EMT) to generate M-circulating tumor cells which are highly invasive, and ② The platelets are supposed to be activated to help M-CTCs survive from the killing of natural killer cells. We had found that the high expression of BCAR1 in lung cancer predicts poor prognosis, and are significantly related to the increasing of M-CTCs and decreasing of NK activity. Additionally, we had found BCAR1\Crk complex can induce EMT and activate platelets via the activation of p38MAPK signaling cascade. We postulated BCAR1\Crk\p38MAPK cascade enhances the occurrence of M-CTCs and immune evasion. We aimed to verify the abovementioned hypothesis via the clinical observation and studies in vivo and vitro. Importantly, we had obtained the McAb of BCAR1 which can block the formation of BCAR1\Crk complex effectively. We will block the BCAR1 signaling cascade simultaneously in cancer cells and platelets by using intracellular BCAR1 antibody so as to avoid the occurrence of M-CTCs and immune evasion. This project is supposed to elucidate the mechanism of tumor recurrence or metastasis. In LAC cases, we should test and screen the expression of BCAR1 in tumor tissue and peripheral blood. Intracellular BCAR1 antibody is supposed to prevent the tumor metastasis.