SOX4-Mediated Transcription Program in Esophageal Adenocarcinoma

SOX4 介导的食管腺癌转录程序

• 批准号: 10662315
• 负责人: Jianwen Que
• 金额: $ 39.63万
• 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/10662315
• 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; Proliferating; 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; Work; adduct; advanced disease; bile salts; cancer cell; cancer initiation; cell transformation; design; drug candidate; drug efficacy; effective therapy; endonuclease; experimental study; gain of function; 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 cells; synergism; 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/总结 过去三十年，食管腺癌 (EAC) 的发病率增加了 600%。治疗 然而，选择是有限的，特别是对于晚期诊断的 EAC。因此，识别新的 治疗目标有必要改善低于 15% 的整体 5 年生存率。这 该提案是 P01 计划的一个组成部分，重点是识别机械脆弱性，同时提供 EAC 治疗的潜在疗法。该应用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变，其抑制具有潜力 阻止EAC的发展。长时间反流，酸性胆汁盐异常反流至下层 食管与巴雷特食管（BE，也称为肠病）的发病密切相关。 化生），一个被认为是 EAC 前体的实体。我们实验室和其他实验室的研究表明 干/祖细胞的恶性转化是食管癌发生过程中发生的关键机制 引发。就 EAC 而言，我们发现新型移行基底细胞 (TBC) 位于 食管胃连接处 (EGJ) 在 Cdx2 过度表达时能够形成巴雷特食管。我们的 初步数据表明，随着 Cdx2 长期过度表达和胆汁酸的增加，EAC 在 EGJ 处形成 反流。然而，驱动干细胞转化和癌症维持的基因调控程序， 仍然难以捉摸。我们发现 SOX4 转录因子在小鼠 EAC 模型中高表达，并且 人类 EAC 活检。 SOX4 蛋白水平降低与癌症生长减少有关。使用 结合 RNA-Seq、ChIP-Seq 和靶向 RNAi 筛选，我们确定 EGFR 和 ELF3 具有潜力 下游靶标介导肿瘤发展中的 SOX4 功能。因此，我们假设 SOX4 是 对于 EAC 启动和维持至关重要，抑制以 SOX4 为中心的信号传导可以 用于 EAC 治疗中的治疗效果。我们的研究与本 P01 中的其他项目很好地结合在一起 我们将测试APE1氧化还原功能和异黄酮蛋白加合物在调节SOX4中的作用。我们 我们设计了三个目标来检验这一假设：（1）确定 SOX4 在 EAC 发展中的作用； (2) 检验 SOX4 在 EAC 中转录调节 EGFR 和 ELF3 的假设； (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模型（例如，SOX4 增益- 和功能丧失）与类器官和患者来源的异种移植模型相结合，以实现这些目标和 测试通过公正筛选确定的两种候选药物。我们的研究将为以下问题提供新颖的见解： EAC 启动和进展的细胞和分子机制，促进 开发致命 EAC 的新疗法。