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:
  • 金额:
    $ 39.63万
  • 依托单位:
  • 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

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

项目成果

期刊论文数量(0)
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Jianwen Que其他文献

Jianwen Que的其他文献

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{{ truncateString('Jianwen Que', 18)}}的其他基金

Tuft Cells Modulate Macrophage Response Following Lung Viral Infection
簇细胞调节肺部病毒感染后的巨噬细胞反应
  • 批准号:
    10453066
  • 财政年份:
    2022
  • 资助金额:
    $ 39.63万
  • 项目类别:
The Enrichment Program
强化计划
  • 批准号:
    10612981
  • 财政年份:
    2022
  • 资助金额:
    $ 39.63万
  • 项目类别:
Gastroesophageal junction stem cells as the origin of Barretts esophagus and cancer
胃食管连接处干细胞是巴雷特食管和癌症的起源
  • 批准号:
    10506097
  • 财政年份:
    2022
  • 资助金额:
    $ 39.63万
  • 项目类别:
Depletion of Barrett's and Esophageal Adenocarcinoma Cells with CRISPR/Cas13d
使用 CRISPR/Cas13d 消除 Barrett 细胞和食管腺癌细胞
  • 批准号:
    10831233
  • 财政年份:
    2022
  • 资助金额:
    $ 39.63万
  • 项目类别:
The Enrichment Program
强化计划
  • 批准号:
    10443140
  • 财政年份:
    2022
  • 资助金额:
    $ 39.63万
  • 项目类别:
SOX4-Mediated Transcription Program in Esophageal Adenocarcinoma
SOX4 介导的食管腺癌转录程序
  • 批准号:
    10407747
  • 财政年份:
    2022
  • 资助金额:
    $ 39.63万
  • 项目类别:
Tuft Cells Modulate Macrophage Response Following Lung Viral Infection
簇细胞调节肺部病毒感染后的巨噬细胞反应
  • 批准号:
    10555330
  • 财政年份:
    2022
  • 资助金额:
    $ 39.63万
  • 项目类别:
Improve Lung Regeneration Through Targeting Tuft Cells Following Viral Infection
通过靶向病毒感染后的簇细胞改善肺再生
  • 批准号:
    10679030
  • 财政年份:
    2021
  • 资助金额:
    $ 39.63万
  • 项目类别:
Improve Lung Regeneration Through Targeting Tuft Cells Following Viral Infection
通过靶向病毒感染后的簇细胞改善肺再生
  • 批准号:
    10471373
  • 财政年份:
    2021
  • 资助金额:
    $ 39.63万
  • 项目类别:
Improve Lung Regeneration Through Targeting Tuft Cells Following Viral Infection
通过靶向病毒感染后的簇细胞改善肺再生
  • 批准号:
    10298186
  • 财政年份:
    2021
  • 资助金额:
    $ 39.63万
  • 项目类别:

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