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
食管腺癌(EAC)的发病率在过去的三十年中增加了600%。治疗
然而,选择是有限的,特别是对于晚期诊断的EAC。因此,确定新的
治疗目标是必要的,以改善总体令人沮丧的5年生存率不到15%。这
该提案是P01计划的一个组成部分,该计划的重点是识别机械脆弱性,同时提供
EAC治疗的潜在疗法。该申请将直接解决新的分子机制,
控制从干细胞到腺癌起始细胞的转变,并且其抑制具有潜在的
阻止EAC的发展。长期反流,其中酸性胆汁盐异常反流到下
食管与Barrett食管(BE,也称为肠源性食管)的发病率密切相关。
化生),一种被认为是EAC前体的实体。我们实验室和其他机构的研究表明,
干/祖细胞的恶性转化是食管癌发生的关键机制,
初始化。在EAC的情况下,我们已经确定了位于基底细胞的新型移行基底细胞(TBC)。
食管-胃交界处(EGJ)能够在Cdx 2过表达时产生Barrett食管。我们
初步数据显示,在延长Cdx 2过表达和胆汁酸刺激后,
倒流然而,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SOX 4转录因子在小鼠EAC模型中高度表达,
人类EAC活检。SOX 4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,我们鉴定了EGFR和ELF 3作为潜在的
在肿瘤发展中介导SOX 4功能的下游靶点。因此,我们假设SOX 4是
这对于EAC的启动和维持至关重要,抑制以SOX 4为中心的信号传导可能是
用于EAC治疗中的治疗增益。我们的研究与本P01中的其他项目结合良好
我们将测试APE 1氧化还原功能和isolevuglandin蛋白加合物在调节SOX 4中的作用。我们
我们设计了三个目标来验证这一假设:(1)确定SOX 4在EAC发育中的作用;(2)
以检验SOX 4在EAC中转录调节EGFR和ELF 3的假设;以及(3)确定
在EAC治疗中S 0X 4抑制的治疗作用。我们将使用多种小鼠模型(例如,SOX 4增益-
和功能丧失)与类器官和患者来源的异种移植模型组合以解决这些目标,
测试通过无偏筛选确定的两种候选药物。我们的研究将为我们提供新的见解
EAC启动和进展的细胞和分子机制,促进
致命EAC的新疗法的发展。
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)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
Jianwen Que其他文献
Jianwen Que的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ 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:
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:
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:
10298186 - 财政年份:2021
- 资助金额:
$ 39.63万 - 项目类别:
相似海外基金
Rational design of rapidly translatable, highly antigenic and novel recombinant immunogens to address deficiencies of current snakebite treatments
合理设计可快速翻译、高抗原性和新型重组免疫原,以解决当前蛇咬伤治疗的缺陷
- 批准号:
MR/S03398X/2 - 财政年份:2024
- 资助金额:
$ 39.63万 - 项目类别:
Fellowship
Re-thinking drug nanocrystals as highly loaded vectors to address key unmet therapeutic challenges
重新思考药物纳米晶体作为高负载载体以解决关键的未满足的治疗挑战
- 批准号:
EP/Y001486/1 - 财政年份:2024
- 资助金额:
$ 39.63万 - 项目类别:
Research Grant
CAREER: FEAST (Food Ecosystems And circularity for Sustainable Transformation) framework to address Hidden Hunger
职业:FEAST(食品生态系统和可持续转型循环)框架解决隐性饥饿
- 批准号:
2338423 - 财政年份:2024
- 资助金额:
$ 39.63万 - 项目类别:
Continuing Grant
Metrology to address ion suppression in multimodal mass spectrometry imaging with application in oncology
计量学解决多模态质谱成像中的离子抑制问题及其在肿瘤学中的应用
- 批准号:
MR/X03657X/1 - 财政年份:2024
- 资助金额:
$ 39.63万 - 项目类别:
Fellowship
CRII: SHF: A Novel Address Translation Architecture for Virtualized Clouds
CRII:SHF:一种用于虚拟化云的新型地址转换架构
- 批准号:
2348066 - 财政年份:2024
- 资助金额:
$ 39.63万 - 项目类别:
Standard Grant
BIORETS: Convergence Research Experiences for Teachers in Synthetic and Systems Biology to Address Challenges in Food, Health, Energy, and Environment
BIORETS:合成和系统生物学教师的融合研究经验,以应对食品、健康、能源和环境方面的挑战
- 批准号:
2341402 - 财政年份:2024
- 资助金额:
$ 39.63万 - 项目类别:
Standard Grant
The Abundance Project: Enhancing Cultural & Green Inclusion in Social Prescribing in Southwest London to Address Ethnic Inequalities in Mental Health
丰富项目:增强文化
- 批准号:
AH/Z505481/1 - 财政年份:2024
- 资助金额:
$ 39.63万 - 项目类别:
Research Grant
ERAMET - Ecosystem for rapid adoption of modelling and simulation METhods to address regulatory needs in the development of orphan and paediatric medicines
ERAMET - 快速采用建模和模拟方法的生态系统,以满足孤儿药和儿科药物开发中的监管需求
- 批准号:
10107647 - 财政年份:2024
- 资助金额:
$ 39.63万 - 项目类别:
EU-Funded
Ecosystem for rapid adoption of modelling and simulation METhods to address regulatory needs in the development of orphan and paediatric medicines
快速采用建模和模拟方法的生态系统,以满足孤儿药和儿科药物开发中的监管需求
- 批准号:
10106221 - 财政年份:2024
- 资助金额:
$ 39.63万 - 项目类别:
EU-Funded
Recite: Building Research by Communities to Address Inequities through Expression
背诵:社区开展研究,通过表达解决不平等问题
- 批准号:
AH/Z505341/1 - 财政年份:2024
- 资助金额:
$ 39.63万 - 项目类别:
Research Grant