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
- 来源:
- 关键词:AbbreviationsAddressAdenocarcinomaAdenocarcinoma CellAnimal ModelBarrett EsophagusBasal CellBile AcidsBiopsyCancer Cell GrowthCell LineCell ProliferationCell SurvivalCellsChIP-seqCollaborationsDataDevelopmentDiagnosisDiseaseDisease ProgressionDistalDown-RegulationDrug usageELF3 geneEnvironmentEpidermal Growth Factor ReceptorEpidermal Growth Factor Receptor Tyrosine Kinase InhibitorEsophageal AdenocarcinomaEsophagusEventFDA approvedFrequenciesGastroesophageal reflux diseaseGeneticGenetic TranscriptionGrowthHealthHumanIn VitroIncidenceIntestinal MetaplasiaKnowledgeLibrariesMaintenanceMalignant - descriptorMalignant NeoplasmsMalignant neoplasm of esophagusMediatingMetaplasiaMetoprololModelingMolecularMusOrganoidsOxidation-ReductionOxidative StressPatientsPharmaceutical PreparationsPrognosisProgram Research Project GrantsProliferatingProteinsRNA InterferenceRNA interference screenRefluxRegulationRoleSOX4 geneSignal TransductionSimple Columnar EpitheliumStomachStratified Squamous EpitheliumSurvival RateTestingTherapeuticTranscriptTranscription CoactivatorWorkadductadvanced diseasebile saltscancer cellcancer initiationcell transformationdesigndrug candidatedrug efficacyeffective therapyendonucleaseexperimental studygain of functionimprovedin vivoin vivo Modelinhibitorinsightknock-downloss of functionmouse modelnew therapeutic targetnoveloverexpressionpatient derived xenograft modelprogramsscreeningstem cellssynergismtargeted treatmenttranscription factortranscriptome sequencingtumortumorigenesis
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.
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。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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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:
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:
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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