Master regulator transcription factors promote esophageal neoplastic evolution

主调控转录因子促进食管肿瘤演化

• 批准号: 10203879
• 负责人: De-Chen Lin
• 金额: $ 38.02万
• 依托单位: CEDARS-SINAI MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-06-01 至 2021-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10203879
• 关键词: 3-Dimensional; ARID1A gene; ATAC-seq; Adenocarcinoma Cell; Barrett Esophagus; Benign; Biological; Biological Assay; Biological Markers; Biological Process; Biology; CRISPR interference; Cell Line; Cell Proliferation; Cell physiology; Cells; ChIP-seq; Chemicals; Chromatin; Chromatin Conformation Capture and Sequencing; Country; Data; Development; Disease; ELF3 gene; Early Intervention; Enhancers; Epigenetic Process; Epithelial Cells; Esophageal Adenocarcinoma; Esophagogastric Junction; Esophagus; European; Event; Evolution; FDA approved; Fatty Acids; Feedback; Foundations; Genes; Genetic Transcription; Genomics; Glean; High Fat Diet; Human; Incidence; Individual; Intervention; Investigation; Lesion; Link; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of esophagus; Mass Spectrum Analysis; Modeling; Molecular; Mutation; Neoplasms; Nuclear Receptors; Obesity; Oncogenic; Organoids; PF4 Gene; PPAR gamma; PPARG gene; Pathway interactions; Pharmaceutical Preparations; Precancerous Conditions; Refractory; Regulation; Regulatory Element; Research; Risk; Risk Factors; Sampling; Signal Pathway; TP53 gene; Testing; Therapeutic; Translating; Treatment Protocols; United States; Xenograft procedure; base; cancer cell; combinatorial; driving force; epigenome; epigenomics; experimental study; genome-wide; high risk; inhibitor/antagonist; insight; interest; lipidomics; loss of function; mouse model; neoplastic; novel; obese patients; premalignant; preventive intervention; profiles in patients; research clinical testing; transcription factor; transcriptome; transcriptome sequencing

PROJECT SUMMARY Esophageal adenocarcinoma (EAC) is one of the deadliest malignancies, and its incidence has strikingly increased 6-8 fold in Western countries (including the United States, UK and several European countries) over the past 4 decades. Despite new insights gained from recent genomic analyses, meaningful therapeutic improvements have not occurred and the 5-year survival of EAC has remained extremely low (~20%). Therefore, alternative research approaches, including advanced epigenomic studies, are desperately needed to understand the molecular basis of EAC for developing novel treatment regimens. Barrett’s esophagus (BE) is a premalignant condition and is considered as the obligate precursor lesion of EAC. During Barrett’s esophagus-associated neoplastic evolution, benign BE first becomes dysplastic and then progresses to EAC. Therefore, BE serves as an ideal pre-malignant model for the investigation of the step-wise neoplastic evolution of esophageal epithelial cells. However, our understanding of the molecular mechanisms promoting BEAN remains limited, with key questions (e.g., the primary drivers for the malignant transformation of BE into EAC) still unaddressed. We and others have shown that malignant transformation is accompanied by genome-wide gains and losses of enhancers and super-enhancers, which are occupied and regulated by upstream master regulator transcription factors (MRTFs). Indeed, our recent studies demonstrated profound alterations in both enhancer usage and MRTF activity between normal gastroesophageal junction (NGEJ), BE and EAC samples. Particularly, we have identified a set of EAC-specific MRTFs (ELF3, KLF5, GATA6, EHF). Pilot experiments have shown that these 4 MRTFs co-occupy hundreds of EAC-specific enhancers and super-enhancers, indicating they may regulate the EAC transcriptome. Moreover, these EAC-specific MRTFs are highly and uniquely expressed in EAC compared with normal GEJ or BE samples and are functionally required for EAC cell proliferation. Based on these findings, we hypothesize that EAC-specific MRTFs directly promote the malignant transformation of BE cells by rewiring enhancers and super-enhancers across the epigenome, activating signaling pathways and cellular processes essential for EAC development. We will test this hypothesis by investigating the biological functions of MRTFs in human BE-derived 3D organoids. In addition, we will study the mechanistic basis of the strong association between obesity and EAC by focusing on the regulatory loop of MRTF and fatty-acid synthesis, which is the key downstream pathway identified by our preliminary data. These investigations promise to establish primary driving forces of BE-associated neoplasia evolution and uncover epigenomic mechanisms underlying esophagus transformation, which will fundamentally transform our insights into the biology of esophageal cancer. More importantly, successful execution of this proposal may identify potential avenue for the prevention and early intervention of EAC by targeting fatty-acid synthesis pathway in the high-risk individuals (e.g., refractory and/or high-grade BE patients) with obese condition.

项目摘要 食道腺癌（EAC）是最致命的恶性肿瘤之一，其发病率惊人 西方国家（包括美国，英国和几个欧洲国家）增加了6-8倍 过去40年。尽管最近的基因组分析获得了新的见解，但有意义的疗法 没有发生改善，EAC的5年生存率仍然非常低（约20％）。所以， 迫切需要采用替代研究方法，包括高级表观基因组学研究 EAC开发新型治疗方案的分子基础。巴雷特的食道（BE）是一个预先的 条件，被认为是EAC的义务前体病变。在巴雷特食管相关的过程中 肿瘤进化，良性首先变成异型症，然后发展为EAC。因此，被当作 用于投资食管上皮的逐步肿瘤演变的理想预防前模型 细胞。但是，我们对促进豆的分子机制的理解仍然有限，密钥 问题（例如，将BE转化为EAC的主要驱动因素）仍然没有解决。 我们和其他人表明，恶性转化是通过全基因组的收益和损失来实现的 增强剂和超级增强剂，由上游主管占领和监管 转录因子（MRTF）。确实，我们最近的研究表明两个增强剂都有深刻的变化 正常胃食管合物（NGEJ），BE和EAC样品之间的使用和MRTF活性。特别， 我们已经确定了一组EAC特异性MRTF（ELF3，KLF5，GATA6，EHF）。飞行员实验表明 这4个MRTF共同占地数百个EAC特异性增强剂和超级增强剂，表明它们可能 调节EAC转录组。此外，这些EAC特异性的MRTF在 与正常的GEJ相比，EAC是EAC细胞增殖需要的，在功能上是必需的。 基于这些发现，我们假设EAC特异性MRTF直接促进恶性肿瘤 通过将增强子和超增强剂重新跨表观基因组重新转换，激活 信号通路和细胞过程对于EAC开发必不可少。我们将通过 研究人类BE衍生的3D器官中MRTF的生物学功能。此外，我们将研究 肥胖与EAC之间密切关联的机理基础是专注于调节循环 MRTF和脂肪酸合成，这是我们初步数据确定的下游途径的关键。这些 调查有望建立与BE相关的肿瘤进化和发现的主要驱动力 食道转化的背后的表观基因组机制，这将从根本上改变我们的见解 进入食道癌的生物学。更重要的是，该提案的成功执行可能会确定 通过靶向脂肪酸合成途径，预防和早期干预EAC的潜在途径 具有肥胖状况的高风险个体（例如难治性和/或高级患者）。