Mechanisms of Epigenetic Plasticity in PDAC

PDAC表观遗传可塑性机制

基本信息

  • 批准号:
    10379399
  • 负责人:
  • 金额:
    $ 48.3万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2021
  • 资助国家:
    美国
  • 起止时间:
    2021-04-01 至 2026-03-31
  • 项目状态:
    未结题

项目摘要

Pancreatic ductal adenocarcinoma (PDAC) is one of the most deadly human cancers and in ~95% of cases driven by oncogenic mutations of Kras. Unfortunately, attempts to directly inhibit oncogenic Kras or Ras effector pathways have been largely ineffective in treating PDAC due to the development of resistance. Yap (Yes-associated-protein), an oncogenic transcription regulator, not only is required for PDAC progression but also confers resistance to extinction of oncogenic Kras signaling and other therapeutic agents in advanced PDAC tumors. Using a next- generation inducible genetic engineered mouse model, we discovered that even though PDAC tumors rely on Yap to maintain the transcriptional output necessary for tumor growth and survival, a subpopulation of tumor cells with stem/progenitor-like characteristics undergo epigenetic reprogramming eventually overcoming their Yap addiction in late stage PDAC. In this grant we propose a multi-faceted effort to elucidate the molecular/cellular drivers of adaptive reprogramming in Yap-ablated, advanced PDAC tumors, and explore novel therapeutic strategies to overcome resistance to Yap blockade. Furthermore, we will use an inducible genetic lineage- tracing model to track how the cancer “stem/progenitor” niches contribute to PDAC invasion, metastasis and resistance to Yap ablation. Together, these experiments will not only provide critical insights into the mechanisms underlying PDAC plasticity, but also inform potential new strategies to overcome therapeutic resistance in PDAC.
胰腺导管腺癌(Pancreatic ductal adencarcinoma, PDAC)是最致命的人类癌症之一,约占95%

项目成果

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Alessandro Gardini其他文献

Alessandro Gardini的其他文献

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{{ truncateString('Alessandro Gardini', 18)}}的其他基金

Mechanisms of Epigenetic Plasticity in PDAC
PDAC表观遗传可塑性机制
  • 批准号:
    10634498
  • 财政年份:
    2021
  • 资助金额:
    $ 48.3万
  • 项目类别:
Mechanisms of Epigenetic Plasticity in PDAC
PDAC表观遗传可塑性机制
  • 批准号:
    10211135
  • 财政年份:
    2021
  • 资助金额:
    $ 48.3万
  • 项目类别:
Role of an Integrator-EGR axis in the regulation of myeloid enhancers (Admin Supp)
Integrator-EGR 轴在骨髓增强子调节中的作用(管理补充)
  • 批准号:
    10007301
  • 财政年份:
    2020
  • 资助金额:
    $ 48.3万
  • 项目类别:
Role of an Integrator-EGR axis in the regulation of myeloid enhancers
Integrator-EGR 轴在骨髓增强子调节中的作用
  • 批准号:
    10534872
  • 财政年份:
    2019
  • 资助金额:
    $ 48.3万
  • 项目类别:
Role of an Integrator-EGR axis in the regulation of myeloid enhancers
Integrator-EGR 轴在骨髓增强子调节中的作用
  • 批准号:
    10310455
  • 财政年份:
    2019
  • 资助金额:
    $ 48.3万
  • 项目类别:
Role of an Integrator-EGR axis in the regulation of myeloid enhancers
Integrator-EGR 轴在骨髓增强子调节中的作用
  • 批准号:
    10748543
  • 财政年份:
    2019
  • 资助金额:
    $ 48.3万
  • 项目类别:
Role of an Integrator-EGR axis in the regulation of myeloid enhancers
Integrator-EGR 轴在骨髓增强子调节中的作用
  • 批准号:
    10536618
  • 财政年份:
    2019
  • 资助金额:
    $ 48.3万
  • 项目类别:
Role of an Integrator-EGR axis in the regulation of myeloid enhancers
Integrator-EGR 轴在骨髓增强子调节中的作用
  • 批准号:
    10064637
  • 财政年份:
    2019
  • 资助金额:
    $ 48.3万
  • 项目类别:
Training Program in Basic Cancer Research
基础癌症研究培训计划
  • 批准号:
    10654720
  • 财政年份:
    1976
  • 资助金额:
    $ 48.3万
  • 项目类别:

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