上皮-间质转化（EMT）过程中细胞重编程的机制

The epithelial-to-mesenchymal transition (EMT) affects critical steps of morphogenesis and tumor metastasis by interconverting epithelial cell type into cells with mesenchymal attributes. EMT programs activated in carcinoma cell enable those cells to acquire cellular traits associated with high-grade malignancy. Moreover, certain epithelial cells that pass through an EMT reprogramming process acquire the self-renewing trait associated with cancer stem cells (CSCs). However, the reprogramming mechanisms of EMT are still poorly understood. In this study, we will search for the essential pathways and key regulators involved in EMT program by using unbiased, genome-wide high throughput approaches including RNAi Library screening, RNA-Sequencing and ChIP-Sequencing techniques, answering questions about overall patterns of reprogramming process of EMT. In our preliminary work, we have constructed a reliable and efficient model cell line which is sensitive to EMT inducers such as TGFb1 and also suitable for high throughput screening strategies. This research will not only elucidate the reprogramming mechanisms that drive and maintain EMT, but also yield promising therapeutic targets and strategies for the prevention of metastasis — the most common fatal consequence of tumorigenesis.

肿瘤转移是肿瘤病人最常见的死亡原因。上皮-间质转化（EMT）过程在肿瘤转移的初始阶段是非常重要和必不可少的。 这个步骤的实质可能归因于一个事件：EMT过程使肿瘤细胞重编程之后具备了干细胞样特性。本项目旨在通过高通量的RNAi Library筛选，RNA-Seq及ChIP-Seq等实验方法基于生物信息学的贝叶斯因果分析模型寻找上皮细胞转化为间质细胞的细胞重编程过程中的关键通路与关键调控因子，以及其启动与维持EMT的分子机制，特别是表观遗传学机制。目前我们已建立了可靠、量化并可实现高通量筛选的对EMT诱导响应的细胞模型，并且在预实验小规模的RNAi筛选获得了成功。通过本项目的实施，阐明EMT过程中细胞重编程的分子机制，建立和完善EMT的表观遗传学研究的新的技术体系，并为恶性肿瘤的转移预警、诊断、治疗和药物筛选提供新思路、新途径和新靶标。

肿瘤转移是肿瘤病人最常见的死亡原因。上皮-间质转化（EMT）过程在肿瘤转移的初始阶段是非常重要和必不可少的。在该项目资助下，我们在表观遗传调控肿瘤EMT机制的方面取得了以下成果，为认识肿瘤发生提供了新的认识并和治疗靶点。成果包括：1）、FOXK2通过募集转录抑制复合物抑制乳腺癌发生发展，该成果2016年在《Cancer Cell》发表；2）、GATA3和ZEB2之间的负反馈调节失常促进乳腺癌转移的机制，这一研究结果发表在2015年的《Cancer Cell》上；3）、SCFJFK降解生长抑制因子ING4促进乳腺癌的发生和发展，这一研究成果于2015年发表在《Genes & Development》上。以上发现不仅为认识肿瘤EMT提供了新的机理上的认识并未其治疗提供了可能的靶点。此外在该项目的支持下，我们的工作以论文形式在《Nature Genetics》和《Molecular Cell》等杂志发表。