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SOX4-Mediated Transcription Program in Esophageal Adenocarcinoma

SOX4 介导的食管腺癌转录程序

基本信息

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
项目类别：
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

项目摘要

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.

抽象/总结