肿瘤细胞和胞外基质的相互作用是否参与调控肺癌的表型可塑性以及肺癌的谱系转变并不清楚。我们前期研究利用LKB1缺失的肺癌小鼠模型结合病理学分析在体内证实肺腺癌向肺鳞癌的转分化，为肺癌表型的可塑性研究奠定坚实的基础。目前我们的初步数据表明在肺腺鳞癌转分化前后胞外基质确实发生了显著的重构。基于此，本项目拟结合动物模型、细胞株以及临床样本来研究肺腺鳞癌转分化中肿瘤细胞和胞外基质的相互作用及其调控机制。我们将利用基因表达谱分析以及基因功能研究来揭示肺腺鳞癌转分化过程中肿瘤细胞和胞外基质的互动过程，鉴定出参与肿瘤细胞和胞外基质互动的关键分子并阐明其作用机制；同时结合临床样本分析来研究肿瘤细胞和胞外基质的相互作用对于临床肺腺鳞癌转分化的理论意义。这些工作将阐明肺腺鳞癌转分化中肿瘤细胞和胞外基质相互作用的重要性及相关机制，为进一步研究肺癌的表型可塑性提供新思路和潜在的治疗新策略。

It remains unclear if and how the dynamic interplay between tumor cells and extracellular matrix (ECM) regulates lung cancer phenotypic plasticity and cell lineage transition during lung tumorigenesis. Taking advantage of Lkb1/Kras lung cancer mouse model, we have previously provided strong evidences to support the exsitence of the de novo transdifferentiation of lung adenocarcinoma (ADC) to squamous cell carcinoma (SCC), which paves way for studies of lung cancer phenotypic plasticity and transdifferentiation. Interestingly, our current data show that extensive ECM remodeling occurs during the process of ADC to SCC transdifferentiation. Based on this, we seek to investigate the interplay between tumor cells and ECM during lung cancer transdifferentiation through integrative studies on mouse models, human cancer cell lines and clinical specimens. With the bioinformatic analyses on the gene expression profile of LKB1-deficient mouse ADC and SCC and following gene functional studies, we aim to uncover the interplay between tumor cells and surrounding ECM during the transition process. Hopefully we will identify those key players involved in this transition process as well as the related molecular regulatory mechanisms. Moreover, we will explore the potential clinical relevance of our findings from animal models. Together, these studies will uncover the fundamental role of the interplay between tumor cells and ECM in regulating lung cancer lineage conversion and provide novel mechanistic insights into lung cancer phenotypic plasticity, which might hold important implication for clinical lung cancer therapies.