癌基因AXL调控肺癌侵袭转移的分子机制研究

Lung cancer is still the leading cause of cancer-related death worldwide. Recently, we developed erlotinib-resistant NSCLC cell models and discovered a novel mechanism of erlotinib resistance involving increased expression/activation of AXL and identified AXL as a promising therapeutic target whose inhibition could prevent or overcome EGFR TKI acquired resistance in EGFR-mutant lung cancer patients (Nature Genetics 2012). We have also observed that AXL plays an important role in cell adhesion, migration and invasion and appears to be a mediator of the epithelial-mesenchymal transition (EMT) phenotype, indicating that AXL may play a key role in metastasis of a subset of lung cancer and is a very promising novel therapeutic target. In current proposal, we will expand on our prior findings to explore studies on the epigenetic and genetic regulation of the expression and activation of AXL in lung cancer. An epigenetic study of the methylation status of the AXL gene promoter will be pursued to identify the mechanism of overexpression in erlotinib-resistant. A comprehensive expression and genetic study of AXL will also be undertaken utilizing primary human non-small cell lung cancer samples. Correlation between AXL overexpression and epigenetic/genetic events and the biological function related to AXL mutations will be analyzed. We will further refine the function of AXL in cellular migration, invasion and metastasis in lung cancer. Cell model systems with high- or low AXL expression will be established and utilized to further explore the molecular basis of the biologic functions that AXL plays. Metastatic lung cancer xenografts in nude mice will be established to verify our in vitro findings using conditional cell lines and bioluminescence imaging. Our studies will provide a comprehensive genetic and functional assessment of AXL as a novel metastasis gene in lung cancer, establish the potential of AXL-targeted therapeutics and will provide the foundation of future translational studies assessing AXL inhibition as a novel treatment target in lung cancer to improve patient outcomes.

肺癌是全球范围内最常见最致死的恶性肿瘤之一。 最近我们在研究肺癌EGFR-TKI治疗产生获得性耐药的机制时发现AXL高表达和激活不仅是肺癌EGFR-TKI耐药的一个新机制，还明显促进耐TKI细胞的EMT转化及粘附，迁移和侵润 (Nature Genetics, 2012)，提示AXL 可能对部分肺癌的转移起重要作用。在本项目中，我们将进一步利用肺癌细胞模型探讨AXL高表达并功能激活的分子机理，并扩展到使用临床肺癌标本系统研究AXL异常激活的遗传学机制，揭示其在肺癌侵润转移中扮演的角色。最后用动物模型研究验证AXL异常激活是否诱导肺癌细胞的侵润和转移，AXL特异性抑制剂能否有效控制AXL活化引起的肺癌转移。我们的研究有望在部分肺癌病人确立AXL为一个新的肺癌转移驱动基因和一个关键的治疗靶标，为临床肺癌分子分型和个体化靶向治疗提供理论依据。

本研究2014年经费下拨到校后正式开始，研究执行期间，适当调整了项目内容，并进行多方面的研究。研究团队依据课题计划，主要工作集中在：1）与美国博士导师合作撰写AXL作为癌症治疗新靶标研究方向的主要成就与进展的综述；2）指导学生完成一篇中文综述--放射组学的兴起和研究进展；3）鼻咽癌伴有腺样体肥大的患者：用磁共振评估原发灶在治疗前后影像学的变化；4）基于超像素的前列腺磁共振（MR）图像三维分割法研究；5）指导学生完成一篇英文综述：放射组学在诊断肺孤立性小结节方面的潜在应用；6）建立分离携带TP53突变的HPV阴性阴茎鳞癌细胞系Penl1及其生物学研究；7）偶联cetuximabd 靶向EGFR荧光纳米探针研究；8）近红外融合镧系元素的碳量子点设计合成及生物成像应用研究；9）发射红外荧光多炔侨联AIE化合物的设计合成及其应用研究；10) 受DNA损伤激活的非编码RNA的表达与食管鳞状细胞癌的不良预后相关研究；11) AXL-GAS6表达与非小细胞肺癌伴发脑转移的预后关系的研究；12) LncRNA XIST通过调节miR-101/EZH2促进食管鳞状细胞癌的恶化；13）糖酵解和AKT（细胞的自我吞噬作用）的联合抑制可克服肺癌生长因子靶向治疗的耐药性研究。..在课题执行期间，研究组正式发表了13篇文章，其中11篇为SCI研究论文，2篇综述；培养了一名博士研究生；通过课题的执行，建立了一支完善的分子影像研究团队。