小鼠肺腺鳞癌转分化类器官模型的建立及表观调控分子机制研究

肺癌是全世界致死率极高的癌症之一，其亚型分类复杂。针对亚型中不同基因突变的治疗方法各有侧重，亚型间谱系开关的存在也影响肿瘤对于药物的响应。实验室先前的工作发现Lkb1缺失的小鼠肿瘤具有腺癌向鳞癌转分化的现象，但谱系转变的机制有待深入研究。本项研究中拟利用类器官技术和KrasLSL-G12D/+;Lkb1flox/flox(KL)小鼠模型建立新的肺腺鳞癌转分化的类器官模型，在此基础上进行转录组测序和染色质开放性测序，通过生物信息学方法整合分析测序数据，来研究Lkb1缺失导致肺癌亚型转变的表观调控分子机制。前期已取得一些重要进展，包括KL小鼠肺腺鳞癌转分化的类器官模型的成功建立，为后续研究表观调控机制奠定了坚实的基础。本项目将建立新的小鼠肺腺鳞癌转分化类器官模型，并对分化过程中存在的表观调控分子机制进行研究，为深入理解肿瘤可塑性提供帮助，为临床治疗具有转分化潜能的肿瘤提供可行性思路。

Lung cancer is one of the leading causes of cancer death worldwide. The heterogeneous subtypes and their driver gene mutations and lineage transition generally affect the drug response. LKB1 is frequently co-mutated with KRAS in Non-Small Cell Lung Cancer. Loss of tumor suppressor gene Lkb1 promotes lung cancer malignant progression and decreases sensitivity to drug treatment. Our previous study showed the adenocarcinoma to squamous cell carcinoma transdifferentiaiton (AST) in KrasLSL-G12D/+;Lkb1flox/flox (KL) mouse model. Yet LKB1 function in lung tumor lineage switch still remains poorly understood. In this study, we plan to establish a new organoid model to mimic AST progression in vitro. We will collect the organoids samples during AST and do sequencing. Based on the integrated analysis with RNA sequencing and ATAC sequencing, we try to explore the epigenetic mechanism that may regulate AST. We have now successfully established the organoid bank of KL lung ADC. Notably, part of Lkb1-deficient ADC-derived organoid lines transdifferentiated into squamous cell carcinoma-like organoids, which laid the foundation for the mechanistic study. Taken together, this work will establish a new organoid model to study the epigenetic regulation during AST, which may enhance our understanding for tumor evolution and provide new strategies to target the tumors with high plasticity.