应用微流控芯片仿生模型研究肺癌及其转移过程对微环境中间质细胞影响的分子机制

Lung cancer metastasis, which involves a series of complicated pathological process, is closely related to the tumor microenvironment. On the one hand, the microenvironment promotes lung cancer cells metastasis; on the other hand, lung cancer cells in turn affect the microenvironment. To confirm the molecular mechanisms of lung cancer and its metastasis impacting on microenvironment, will cut off the underlying pathways which involved in the improvement of seeds on the soil and thus may provide a novel therapeutic target for lung cancer patients. But now it is difficult to mimic the real lung tumor microenvironment depending on the existing research techniques, also the reliability needs to be improved. Before our group had successfully simulated the lung cancer microenvironment with microfluidic chip technology and applied it in many research fields such as individual treatment of lung cancer, lung cancer invasion and metastasis and the malignant transformation of chronic lung inflammation. Herein, based on the above new microfluidic platform, the project intends to construct a bionic microfluidic chip lung physical model, a bionic microfluidic chip lung cancer model and metastasis model including targeted organs brain, bone, liver etc in order to reproduce the whole pathological process of lung tumorgenesis and metastasis on the microfluidic chip. Simultaneously, to investigate the functional changes of main stromal cells macrophage and fibroblast submerged in the tumor metastasis microenvironment by means of the superiority of microfluidic chip high throughput and integration and further clarify the related molecular mechanisms of lung cancer metastasis impacting on microenvironment. Finally animal testing will be used to qualify the above results gained from the bionic microfluidic lung cancer metastasis model. What’s more, this project will fill the research blank of bionic microfluidic lung cancer pathological model and provide a new approach for medicine study instead of animal testing.

肺癌转移涉及一系列复杂的病理过程，与微环境密切相关。肺癌细胞一方面依赖微环境促进转移，另一方面又对微环境产生影响。明确肺癌及转移对微环境影响的分子机制，将有可能切断"种子"改造"土壤"的路径，为肺癌患者提供新的治疗靶点。但现有研究手段难以真实模拟肺癌微环境，其可靠性也有待提高。本课题组已利用微流控芯片技术模拟肺癌微环境，进行了肺癌个体化治疗、肺癌侵袭转移及肺部慢性炎症恶性转化等研究，本项目拟在此基础上，进一步构建仿生芯片肺生理模型、肺癌模型及脑、肝、骨等靶器官转移模型，在芯片平台再现肺癌发生及转移的病理过程；同时，利用芯片高通量、集成化优势，检测肺癌转移过程微环境中两大类主要间质细胞巨噬细胞和成纤维细胞的功能变化，明确肺癌转移影响微环境的分子机制，并通过动物实验对仿生芯片肺癌转移研究结果加以验证。该项目还将填补目前仿生芯片肺病理模型的研究空白，取代传统动物实验，为医学研究提供新的技术手段。

肺癌是全球发病率和死亡率增长最快、对人类健康和生命威胁最大的恶性肿瘤。肺癌的高死亡率与肺癌极易转移密切相关。肺癌转移涉及游离、迁移、侵袭、适应和重新粘附等一系列复杂的病理过程，这与肿瘤细胞所存在的微环境息息相关。肺癌细胞一方面依赖微环境促进转移，另一方面又对微环境产生影响。明确肺癌转移对微环境影响的分子机制，将有可能切断“种子”改造“土壤”的路径，为肺癌患者提供新的治疗靶点。但现有研究手段难以真实模拟肺癌微环境，其可靠性也有待提高。因此，本项目拟利用微流控芯片技术进行肺癌转移过程对微环境中间质细胞影响的分子机制研究。首先，我们利用微流控芯片技术构建仿生肺癌多器官转移模型；其次，在此模型基础上进行了肺癌转移过程对微环境中间质细胞影响的分子机制研究；最后利用动物模型重现肺癌转移及对微环境影响过程。经过为期五年的研究工作，我们成功构建了仿生肺癌多器官转移模型，实现了肺癌细胞，血管内皮细胞、巨噬细胞、成纤维细胞等间质细胞，肝、脑、骨等多种靶器官细胞的动态联合培养，再现了肺癌生长、侵袭及转移全过程，填补了目前仿生芯片肺癌模型及肿瘤多器官转移模型的国内外研究空白，为医学研究提供新的技术手段；同时，利用蛋白组学、转录组学和代谢组学等技术手段，锁定肺癌发生及转移过程中与微环境中间质细胞相互影响的关键分子，从而进一步明确肺癌转移的分子机制，为肺癌治疗提供了新的治疗靶点。本项目利用微流控芯片技术低消耗、高通量、模拟体内环境等优势成功构建了仿生芯片肺癌转移模型平台，同时在此平台基础上发现了较为重要的分子机制。本项目目前已发表SCI论文17篇，申请专利6项，荣获科研奖项5项，培养博士后2人、博士研究生13人和硕士研究生21人。