肿瘤细胞与胞外基质的相互作用调控肺腺癌向鳞癌转分化的作用及其分子机制

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.

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。

围绕肿瘤细胞与胞外基质的相互作用调控肺腺癌向鳞癌转分化的作用及其分子机制取得一系列原创性的科研进展。项目资助期间作为通讯或共同通讯作者在Cancer Cell、Nature Genetics、J Clin Invest、PNAS等期刊发表项目标注论文18篇，申请专利1项。科研成果包括：1）利用LKB1缺失的小鼠肺癌模型，揭示活性氧簇在调控肺腺鳞癌转分化及耐药中发挥重要作用。KL小鼠肺腺癌中ROS的水平明显高于肺鳞癌，降低ROS水平可抑制肺腺鳞癌转分化。肺腺癌中ROS异常积累源于戊糖磷酸途径下调和脂肪酸氧化通路失活引起的氧化还原态失衡。而诱导ROS可以促进肺腺鳞癌转分化，并促进肿瘤耐药；2）揭示胞外基质的缺失以不依赖于肿瘤细胞内LKB1信号通路失活的方式参与促进肺腺鳞癌转分化的进程；3）收集了KL小鼠不同进展阶段的肿瘤样本，利用动态临界理论模型，揭示肺腺鳞癌转分化过程中的关键临界点及其调控通路；4）利用CRISPR/Cas9技术在体内水平证实Wnt/β-catenin通路在肺腺鳞癌转分化进程中发挥重要的负向调控作用；5）围绕“肺腺鳞癌转分化与肿瘤耐药”这一主题撰写综述论文，对肺腺鳞癌转化在肿瘤治疗耐药中的作用及其临床关联进行系统总结和展望。