Role of hypoxia in fibroblast reprogramming in pancreatic cancer

缺氧在胰腺癌成纤维细胞重编程中的作用

基本信息

  • 批准号:
    10748608
  • 负责人:
  • 金额:
    $ 4.08万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2023
  • 资助国家:
    美国
  • 起止时间:
    2023-09-01 至 2026-08-31
  • 项目状态:
    未结题

项目摘要

PROJECT SUMMARY Pancreatic ductal adenocarcinoma (PDAC) is a prevalent form of pancreatic cancer, accounting for about 90% of all cases of this disease. PDAC is highly fatal, where mortality closely parallels incidence, primarily due to the inability to diagnose PDAC at early stages and resistance to all existing treatments. Besides genetic changes in tumor cells, the tumor microenvironment plays a key role in tumor initiation, progression, and therapeutic resistance. PDAC is notable for its dense desmoplastic stroma, consisting of extracellular matrix, cancer- associated fibroblasts (CAFs), and immune cells. Another notable feature of the PDAC microenvironment is hypoxia, a condition of insufficient oxygen availability. Although hypoxia leads to adaptive responses in both cancer cells and stromal cells, the effects of hypoxia and hypoxia-inducible factor 1ɑ (HIF1ɑ), a master regulator of hypoxic adaptation, on the PDAC stroma and tumor-stroma interactions are not fully understood. We have recently found that inflammatory CAFs (iCAFs), a CAF subset producing high levels of inflammatory cytokines, are linked to the hypoxia-related gene signature and the HIF1 signaling pathway in human and mouse PDAC. By exposing 3D cocultures of pancreatic tumor cells and fibroblasts to either hypoxia or normoxia, we demonstrated that hypoxia promotes iCAF formation via IL1ɑ secreted from tumor cells. Importantly, the presence of hypoxic fibroblasts further elevated IL1ɑ levels in tumor cells, implicating hypoxia as a modulator of bidirectional interactions between tumor cells and fibroblasts. Based on these data, I hypothesize that hypoxia promotes iCAF formation by modulating bidirectional interactions between tumor cells and fibroblasts in PDAC. In Specific Aim 1, I will determine how hypoxia induces IL1ɑ expression in tumor cells via fibroblasts by using a three-dimensional (3D) coculture system of pancreatic tumor cells and fibroblasts and exposing the coculture to either hypoxia or normoxia. In Specific Aim 2, I will determine whether and how fibroblast HIF1ɑ regulates tumor cell-fibroblast interactions and pancreatic tumorigenesis by using 3D cocultures of tumor cells and fibroblasts deficient of HIF1ɑ, and using mouse models lacking fibroblast expression of HIF1ɑ. My work will identify the molecular mechanisms underlying hypoxic regulation of cancer cell-CAF crosstalk. In addition, my studies will determine how activation of HIF1ɑ within CAFs regulates the tumor stroma and PDAC progression, which will inform targeting fibroblast HIF1ɑ as a potential therapeutic avenue to treat PDAC patients.
项目摘要 胰腺导管腺癌(PDAC)是胰腺癌的一种常见形式,约占90% 所有这种疾病的病例PDAC是高度致命的,其中死亡率与发病率密切平行,主要是由于 不能在早期诊断PDAC,并且对所有现有治疗都有抵抗力。除了基因变化, 肿瘤微环境在肿瘤的发生、发展和治疗中起着关键作用, 阻力PDAC以其致密的促结缔组织增生基质而闻名,该基质由细胞外基质、癌细胞和肿瘤细胞组成。 相关的成纤维细胞(CAF)和免疫细胞。PDAC微环境的另一个显著特征是 缺氧,氧气供应不足的状况。虽然缺氧导致适应性反应,在这两个 癌细胞和基质细胞,缺氧和缺氧诱导因子1 β(HIF 1 β),一个主调节因子的作用, 缺氧适应,对PDAC基质和肿瘤-基质相互作用还没有完全了解。我们有 最近发现,炎性CAF(iCAF),一种产生高水平炎性细胞因子的CAF亚群, 与人类和小鼠PDAC中的缺氧相关基因标记和HIF 1信号通路有关。 通过将胰腺肿瘤细胞和成纤维细胞的3D共培养物暴露于缺氧或常氧条件下, 证明缺氧通过肿瘤细胞分泌的IL 1 β促进iCAF形成。重要的是 缺氧成纤维细胞的存在进一步升高了肿瘤细胞中的IL-1 β水平,表明缺氧是肿瘤细胞中IL-1 β的调节剂。 肿瘤细胞和成纤维细胞之间的双向相互作用。基于这些数据,我假设缺氧 通过调节PDAC中肿瘤细胞和成纤维细胞之间的双向相互作用促进iCAF形成。 在具体目标1中,我将通过使用一种新的方法来确定缺氧如何通过成纤维细胞诱导肿瘤细胞中IL 1 β的表达。 胰腺肿瘤细胞和成纤维细胞的三维(3D)共培养系统,并将共培养物暴露于 缺氧或常氧。在具体目标2中,我将确定成纤维细胞HIF 1 α是否以及如何调节肿瘤 通过使用肿瘤细胞和成纤维细胞的3D共培养物的细胞-成纤维细胞相互作用和胰腺肿瘤发生 缺乏HIF 1 α的小鼠模型,以及使用缺乏HIF 1 α的成纤维细胞表达的小鼠模型。我的工作将确定 癌细胞缺氧调节的分子机制-CAF串扰。此外,我的研究将 确定CAFs中HIF 1 α的激活如何调节肿瘤基质和PDAC进展,这将 告知靶向成纤维细胞HIF 1 α作为治疗PDAC患者的潜在治疗途径。

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 }}

Tenzin Ngodup其他文献

Tenzin Ngodup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 }}

相似海外基金

Unraveling the Dynamics of International Accounting: Exploring the Impact of IFRS Adoption on Firms' Financial Reporting and Business Strategies
揭示国际会计的动态:探索采用 IFRS 对公司财务报告和业务战略的影响
  • 批准号:
    24K16488
  • 财政年份:
    2024
  • 资助金额:
    $ 4.08万
  • 项目类别:
    Grant-in-Aid for Early-Career Scientists
Mighty Accounting - Accountancy Automation for 1-person limited companies.
Mighty Accounting - 1 人有限公司的会计自动化。
  • 批准号:
    10100360
  • 财政年份:
    2024
  • 资助金额:
    $ 4.08万
  • 项目类别:
    Collaborative R&D
Accounting for the Fall of Silver? Western exchange banking practice, 1870-1910
白银下跌的原因是什么?
  • 批准号:
    24K04974
  • 财政年份:
    2024
  • 资助金额:
    $ 4.08万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
CPS: Medium: Making Every Drop Count: Accounting for Spatiotemporal Variability of Water Needs for Proactive Scheduling of Variable Rate Irrigation Systems
CPS:中:让每一滴水都发挥作用:考虑用水需求的时空变化,主动调度可变速率灌溉系统
  • 批准号:
    2312319
  • 财政年份:
    2023
  • 资助金额:
    $ 4.08万
  • 项目类别:
    Standard Grant
A New Direction in Accounting Education for IT Human Resources
IT人力资源会计教育的新方向
  • 批准号:
    23K01686
  • 财政年份:
    2023
  • 资助金额:
    $ 4.08万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
An empirical and theoretical study of the double-accounting system in 19th-century American and British public utility companies
19世纪美国和英国公用事业公司双重会计制度的实证和理论研究
  • 批准号:
    23K01692
  • 财政年份:
    2023
  • 资助金额:
    $ 4.08万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
An Empirical Analysis of the Value Effect: An Accounting Viewpoint
价值效应的实证分析:会计观点
  • 批准号:
    23K01695
  • 财政年份:
    2023
  • 资助金额:
    $ 4.08万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
Accounting model for improving performance on the health and productivity management
提高健康和生产力管理绩效的会计模型
  • 批准号:
    23K01713
  • 财政年份:
    2023
  • 资助金额:
    $ 4.08万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
New Role of Not-for-Profit Entities and Their Accounting Standards to Be Unified
非营利实体的新角色及其会计准则将统一
  • 批准号:
    23K01715
  • 财政年份:
    2023
  • 资助金额:
    $ 4.08万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
Improving Age- and Cause-Specific Under-Five Mortality Rates (ACSU5MR) by Systematically Accounting Measurement Errors to Inform Child Survival Decision Making in Low Income Countries
通过系统地核算测量误差来改善特定年龄和特定原因的五岁以下死亡率 (ACSU5MR),为低收入国家的儿童生存决策提供信息
  • 批准号:
    10585388
  • 财政年份:
    2023
  • 资助金额:
    $ 4.08万
  • 项目类别:
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了