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:10407747
- 负责人:
- 金额:$ 40.67万
- 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 GrantsProteinsRNA InterferenceRNA interference screenRefluxRegulationRoleSOX4 geneSignal TransductionSimple Columnar EpitheliumStomachStratified Squamous EpitheliumSurvival RateTestingTherapeuticTranscriptTranscription CoactivatorTransitional EpitheliumWorkadductadvanced diseasebile saltscancer cellcancer initiationcell transformationdesigndrug candidatedrug efficacyeffective therapyendonucleaseexperimental studyimprovedin vivoin vivo Modelinhibitorinsightknock-downloss of functionmouse modelnew therapeutic targetnoveloverexpressionpatient derived xenograft modelprogramsscreeningstemstem cellstargeted 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/摘要
食管腺癌(EAC)的发病率在过去的三十年里上升了600%。治疗
然而,选择是有限的,特别是对于晚期诊断的EACS。因此,识别新的
治疗目标是必要的,以提高总体惨淡的5年存活率不到15%。这
建议书是P01计划的组成部分,重点是识别机制漏洞,同时提供
EAC治疗的潜在治疗方法。这项申请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化及其抑制作用
以阻止EAC的发展。长时间的反流,酸性胆盐异常地回流到下部
食道与Barrett‘s食道(BE,又称肠道)的发生密切相关
(化生),一种被认为是食道癌前驱的实体。我们实验室和其他实验室的研究表明
干细胞/祖细胞恶性转化是食道癌发生的重要机制
入会仪式。在EAC的情况下,我们已经确定了新的过渡性基底细胞(TBC)位于
食道-胃交界处(EGJ)能够在CDX2过表达的情况下产生Barrett‘s食道。我们的
初步数据显示,在长期的cdx2过度表达和胆汁酸的作用下,eac在EGJ发展。
回流。然而,驱动干细胞转化和癌症维持的基因调控计划,
仍然难以捉摸。我们发现Sox4转录因子在小鼠EAC模型和
人类EAC活组织检查。Sox4蛋白水平的降低与癌症生长的减少有关。使用
结合RNA-Seq、ChIP-Seq和靶向RNAi筛选,我们确定了EGFR和ELF3是潜在的
下游靶点介导Sox4在肿瘤发生中的作用。因此,我们假设Sox4是
对EAC启动和维护至关重要,并且抑制以SOX4为中心的信令可能是
在EAC治疗中用于治疗收益。我们的研究与P01中的其他项目很好地结合在一起
我们还将测试APE1氧化还原功能和异紫藤素蛋白加合物在调节Sox4中的作用。我们
我设计了三个目的来检验这一假说:(1)确定Sox4在EAC发育中的作用;(2)
检验Sox4转录调控EAC中EGFR和ELF3的假设;以及(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型号(例如,Sox4 Gain-
和功能丧失)与器官和患者来源的异种移植模型相结合,以满足这些目标和
测试通过无偏见筛选确定的两种候选药物。我们的研究将提供新的见解
EAC启动和发展的细胞和分子机制,促进EAC
致命EAC的新治疗方法的发展。
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:
$ 40.67万 - 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:
$ 40.67万 - 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:
10662315 - 财政年份:2022
- 资助金额:
$ 40.67万 - 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:
$ 40.67万 - 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:
$ 40.67万 - 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:
$ 40.67万 - 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:
$ 40.67万 - 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:
$ 40.67万 - 项目类别:
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