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/摘要 在过去的三十年中，食管腺癌（EAC）的事件增加了600％。治疗 但是，选项受到限制，尤其是对于晚期诊断的EAC。那，确定新的 为了提高总体惨淡的5年生存率小于15％，需要治疗靶标。这 提案是P01计划的组成部分，该计划旨在确定机械脆弱性，同时提供机械脆弱性 EAC治疗的潜在疗法。该应用将直接解决新的分子机制 控制从干细胞到腺癌发射细胞的过渡，其抑制作用具有潜力 阻止EAC开发。长时间的反射x，其中酸性胆汁盐绝对反射到下部 食道与Barrett的食道事件密切相关（也称为肠道 Metaplasia），一个被认为是EAC的前体的实体。我们实验室和其他人的研究表明 茎/祖细胞的恶性转化是食管癌期间发生的关键机制 引发。在EAC的情况下，我们已经确定了位于 食管宿舍结（EGJ）能够在CDX2过表达时产生Barrett的食管。我们的 初步数据表明，EAC在延长CDX2过表达和胆汁酸后在EGJ开发 回流。但是，驱动干细胞转化和癌症维持的遗传调节计划，但是 仍然难以捉摸。我们发现Sox4转录因子在小鼠EAC模型中高度表达，并且 人类EAC活检。 Sox4蛋白水平降低与癌症生长降低有关。使用 RNA-seq，chip-seq和靶向RNAi筛选的组合，我们将EGFR和ELF3确定为电势 下游目标在肿瘤发育中介导SOX4功能。因此，我们假设Sox4是 对于EAC计划和维护至关重要，并且以Sox4为中心的信号传导可能是 用于EAC治疗中的治疗益处。我们的研究与该P01的其他项目很好地融合 我们将测试APE1氧化还原函数和异戊瓜蛋白加合物在调节SOX4中的作用。我们 已经设计了三个目的来检验这一假设：（1）确定SOX4在EAC开发中的作用； （2） 为了测试Sox4在EAC中调节EGFR和ELF3的假设； （3）确定 SOX4抑制在EAC治疗中的治疗作用。我们将使用多个鼠标模型（例如Sox4增益 - 功能丧失）与类器官和患者衍生的Xenographic模型相结合，以解决这些目标和 测试通过公正屏幕确定的两种候选药物。我们的研究将为您提供新的见解 EAC计划和进展的基础的细胞和分子机制，支持 致命EAC的新型治疗方法的发展。