SOX4-Mediated Transcription Program in Esophageal Adenocarcinoma

SOX4 介导的食管腺癌转录程序

• 批准号: 10407747
• 负责人: Jianwen Que
• 金额: $ 40.67万
• 依托单位: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-08 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10407747
• 关键词: Abbreviations; Address; Adenocarcinoma; Adenocarcinoma Cell; Animal Model; Barrett Esophagus; Basal Cell; Bile Acids; Biopsy; Cancer Cell Growth; Cell Line; Cell Proliferation; Cell Survival; Cells; ChIP-seq; Collaborations; Data; Development; Diagnosis; Disease; Disease Progression; Distal; Down-Regulation; Drug usage; ELF3 gene; Environment; Epidermal Growth Factor Receptor; Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor; Esophageal Adenocarcinoma; Esophagus; Event; FDA approved; Frequencies; Gastroesophageal reflux disease; Genetic; Genetic Transcription; Growth; Health; Human; In Vitro; Incidence; Intestinal Metaplasia; Knowledge; Libraries; Maintenance; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of esophagus; Mediating; Metaplasia; Metoprolol; Modeling; Molecular; Mus; Organoids; Oxidation-Reduction; Oxidative Stress; Patients; Pharmaceutical Preparations; Prognosis; Program Research Project Grants; Proteins; RNA Interference; RNA interference screen; Reflux; Regulation; Role; SOX4 gene; Signal Transduction; Simple Columnar Epithelium; Stomach; Stratified Squamous Epithelium; Survival Rate; Testing; Therapeutic; Transcript; Transcription Coactivator; Transitional Epithelium; Work; adduct; advanced disease; bile salts; cancer cell; cancer initiation; cell transformation; design; drug candidate; drug efficacy; effective therapy; endonuclease; experimental study; improved; in vivo; in vivo Model; inhibitor; insight; knock-down; loss of function; mouse model; new therapeutic target; novel; overexpression; patient derived xenograft model; programs; screening; stem; stem cells; targeted treatment; transcription factor; transcriptome sequencing; tumor; tumorigenesis

ABSTRACT/SUMMARY The incidence of esophageal adenocarcinoma (EAC) has increased 600% in the last three decades. Treatment options, however, are limited, especially for EACs diagnosed at the late stages. Thus, identifying new therapeutic targets is necessary to improve the overall dismal 5-year survival rate of less than 15%. This proposal is an integral part of a P01 Program focused on identifying mechanistic vulnerability while providing potential therapy for EAC treatment. This application will directly address novel molecular mechanisms that control the transition from stem cells to adenocarcinoma-initiating cells and whose inhibition has the potential to block EAC development. Prolonged reflux where acidic bile salts abnormally refluxate into the lower esophagus is closely associated with the incidence of Barrett’s esophagus (BE, also known as intestinal metaplasia), an entity considered as the precursor to EAC. Studies from our lab and others have shown that malignant transformation of stem/progenitor cells is a critical mechanism that occurs during esophageal cancer initiation. In the case of EAC, we have identified that the novel transitional basal cells (TBCs) located at the esophageal-gastric junction (EGJ) are able to generate Barrett’s esophagus upon Cdx2 overexpression. Our preliminary data show that EAC develops at the EGJ following prolonged Cdx2 overexpression and bile acid reflux. The genetic regulatory program that drives stem cell transformation and cancer maintenance, however, remains elusive. We found that SOX4 transcription factor is highly expressed in mouse EAC models and human EAC biopsies. Decreased levels of SOX4 protein are associated with reduced cancer growth. Using a combination of RNA-Seq, ChIP-Seq, and targeted RNAi screening, we identified EGFR and ELF3 as potential downstream targets mediating SOX4 function in tumor development. Therefore, we hypothesize that SOX4 is critical for EAC initiation and maintenance and that suppressing SOX4-centered signaling can be utilized for therapeutic gains in EAC treatment. Our studies integrate well with other projects in this P01 and we will test the roles of APE1 redox function and isolevuglandin protein adducts in regulating SOX4. We have designed three aims to test this hypothesis: (1) To determine the role of SOX4 in EAC development; (2) to test the hypothesis that SOX4 transcriptionally regulates EGFR and ELF3 in EAC; and (3) to determine the therapeutic role of SOX4 inhibition in EAC treatment. We will use multiple mouse models (e.g., SOX4 gain- and loss-of-function) combined with organoid and patient-derived xenograft models to address these aims and test two candidate drugs identified through an unbiased screen. Our studies will provide novel insights into the cellular and molecular mechanisms underlying the EAC’s initiation and progression, facilitating the development of novel treatments of deadly EAC.

摘要/摘要 食管腺癌(EAC)的发病率在过去的三十年里上升了600%。治疗 然而，选择是有限的，特别是对于晚期诊断的EACS。因此，识别新的 治疗目标是必要的，以提高总体惨淡的5年存活率不到15%。这 建议书是P01计划的组成部分，重点是识别机制漏洞，同时提供 EAC治疗的潜在治疗方法。这项申请将直接解决新的分子机制， 控制干细胞向腺癌起始细胞的转化及其抑制作用 以阻止EAC的发展。长时间的反流，酸性胆盐异常地回流到下部 食道与Barrett‘s食道(BE，又称肠道)的发生密切相关 (化生)，一种被认为是食道癌前驱的实体。我们实验室和其他实验室的研究表明 干细胞/祖细胞恶性转化是食道癌发生的重要机制 入会仪式。在EAC的情况下，我们已经确定了新的过渡性基底细胞(TBC)位于 食道-胃交界处(EGJ)能够在CDX2过表达的情况下产生Barrett‘s食道。我们的 初步数据显示，在长期的cdx2过度表达和胆汁酸的作用下，eac在EGJ发展。 回流。然而，驱动干细胞转化和癌症维持的基因调控计划， 仍然难以捉摸。我们发现Sox4转录因子在小鼠EAC模型和 人类EAC活组织检查。Sox4蛋白水平的降低与癌症生长的减少有关。使用 结合RNA-Seq、ChIP-Seq和靶向RNAi筛选，我们确定了EGFR和ELF3是潜在的 下游靶点介导Sox4在肿瘤发生中的作用。因此，我们假设Sox4是 对EAC启动和维护至关重要，并且抑制以SOX4为中心的信令可能是 在EAC治疗中用于治疗收益。我们的研究与P01中的其他项目很好地结合在一起 我们还将测试APE1氧化还原功能和异紫藤素蛋白加合物在调节Sox4中的作用。我们 我设计了三个目的来检验这一假说：(1)确定Sox4在EAC发育中的作用；(2) 检验Sox4转录调控EAC中EGFR和ELF3的假设；以及(3)确定 Sox4抑制在EAC治疗中的治疗作用。我们将使用多种鼠标型号(例如，Sox4 Gain- 和功能丧失)与器官和患者来源的异种移植模型相结合，以满足这些目标和 测试通过无偏见筛选确定的两种候选药物。我们的研究将提供新的见解 EAC启动和发展的细胞和分子机制，促进EAC 致命EAC的新治疗方法的发展。