非小细胞肺癌中乙酰胆碱受体α7nAChR诱导癌相关成纤维细胞代谢重编程及其影响肿瘤微环境的病理机制研究

Cigarrate is the major cause of lung cancer, of which nicotine is the primary cancer inducer. Tumor microenvironment renders the condition for the proliferation and metastasis of cancer cells and subsequently the malignant progression of lung cancer. During the establishment of tumor microenvironment, cancer-associated fibroblast (CAF) plays the critical role. This programme is focused on the role of nicotine and nicotinic receptor α7nAChR on tumor microenvironment and the development of non-small cell lung cancer (NSCLC). Our previous experiments showed that α7nAChR was significantly upregulated in NSCLC tissue and CAF. Activation of α7nAChR induced metablic reprogramming in fibroblast, which mediates the malignant transformation. What's more, α7nAChR activation promoted the secretory function of CAF. Based on the previous studies, we proposed to further explore the specific mechanism of α7nAChR on NSCLC progression by deciphering its role in CAF transformation and function, furthermore, its role in tumor microenvironment regulation. Therefore, to provide theoretical and experimental basis for novel strategies in the treatment and diagnosis of NSCLC via targeting α7nAChR.

吸烟是肺癌重要诱因，烟碱是其主要致癌成分。肿瘤微环境是肺癌细胞增殖与转移等恶性进展的重要条件，而癌相关成纤维细胞（CAF）是构建与维持肿瘤微环境的关键细胞。本项目聚焦的科学问题是烟碱与受体α7nAChR对肿瘤微环境的影响和对非小细胞肺癌恶性进程的作用机制及其干预策略。预初实验已发现α7nAChR在非小细胞肺癌肿瘤组织及CAF中表达显著升高；活化α7nAChR可诱导成纤维细胞发生介导其恶性转化的代谢重编程，并促进CAF分泌调控肿瘤微环境的因子。为此，项目组拟系统研究和明确烟碱-α7nAChR信号异常对肿瘤微环境和非小细胞肺癌恶性进程的影响；揭示α7nAChR通过诱导代谢重编程促进CAF恶性转化、通过调控CAF细胞功能促进形成免疫抑制及促转移的肿瘤微环境的机制。藉此，明晰烟碱促进非小细胞肺癌的病理机制，为形成以α7nAChR为核心靶标的非小细胞肺癌防治新策略和临床检测新指标提供理论和实验依据。

本项目以烟碱型乙酰胆碱受体α7nAChR为切入点，系统研究α7nAChR诱导癌相关成纤维细胞代谢重编程及其影响肿瘤微环境的作用与机制，明确NSCLC患者癌组织的α7nAChR的表达增强，解析α7nAChR对CAF调控肺癌细胞增殖和迁移；明确α7nAChR通过调控去泛素化酶UCHL1，调控葡萄糖摄取和线粒体自噬诱导CAF代谢重编程；建立NSCLC耐药细胞株，解析耐药细胞株中UCHL1和耐药细胞株多药耐药关系，明确UCHL1通过上调TS表达修复DNA损伤介导PEM耐药。抑制UCHL1活性逆转H1299/PEM细胞对PEM耐药的机制；阐明NSCLC中烟碱-乙酰胆碱受体α7nAChR通过诱导代谢重编程介导的CAF转化，并参与构建与维持免疫抑制、促转移的肿瘤微环境的病理作用与机制；明确α7nAChR与NSCLC临床病理特征的相关性及其作为临床NSCLC评价新指标的潜能，为形成以α7nAChR为核心的NSCLC防治新策略提供理论基础和实验依据。发表标注资助的SCI论文5篇，培养硕博士研究生5名。