Investigating GLI transcription factors as regulators of the pancreatic cancer microenvironment

研究 GLI 转录因子作为胰腺癌微环境的调节剂

基本信息

  • 批准号:
    10681714
  • 负责人:
  • 金额:
    $ 59.12万
  • 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:
    2023-05-01 至 2028-04-30
  • 项目状态:
    未结题

项目摘要

PROJECT SUMMARY/ABSTRACT Pancreatic cancer is a deadly human malignancy, with a five-year survival rate of 11%. Further, the incidence of pancreatic cancer is rising and is projected to be the second-leading cause of cancer-related death in the United States by 2030. The increasing occurrence of this disease, combined with the lack of effective treatments, creates an urgent need to better understand the factors that contribute to the progression of pancreatic cancer, and to develop improved therapies that will tangibly benefit human health. One pathway that has been implicated in pancreatic cancer for nearly twenty years is the Hedgehog (HH) signaling pathway. Initial work demonstrated that HH ligand expression increases during pancreatic cancer progression, while more recent studies have found that tumor-derived HH ligands signal in a paracrine fashion to activate HH signaling in pancreatic fibroblasts. As with many efforts to treat pancreatic cancer, clinical trials with HH pathway inhibitors have proven ineffective, or actually sped disease progression. However, work from our laboratories has identified three novel findings regarding the role of HH signaling in pancreatic cancer progression: First, we have found that the levels of HH signaling can determine whether HH signaling promotes or inhibits pancreatic tumor growth; Second, we have recently discovered that HH pathway inhibition can alter the fibroblast composition in the pancreatic cancer microenvironment; Third, our data indicate that HH pathway inhibition dramatically alters immune composition, through altered fibroblast-immune crosstalk. Together, these data suggest that an improved understanding of the role of HH signaling in the pancreatic cancer microenvironment, including HH-dependent fibroblast-immune crosstalk will provide an opportunity to advance the development of more effective pancreatic cancer treatment options. In this proposal, we will investigate the role of glioma-associated proteins (GLIs), a family of three proteins (GLI1-3) that are the transcriptional effectors of the HH signaling pathway, in pancreatic cancer progression. Specifically, we will use novel pancreatic fibroblast cell lines lacking Gli1, Gli2 or Gli3 individually and in combination to investigate the consequences on pancreatic tumor growth in co-transplantation assays. We will also investigate Gli deletion in vivo using two different Cre driver alleles (PdgfraCreER and Gli1CreER) in a novel, FlpO-driven mouse model of pancreatic cancer progression. Further, we will investigate GLI- dependent effects on fibroblast-immune crosstalk through assessment of macrophage and T cell migration, polarization and function. Finally, we will define GLI transcriptional targets in pancreatic fibroblasts both in vitro and in vivo, in the normal pancreas and in the context of pancreatic cancer, using a novel set of epitope-tagged knock-in alleles. This work will advance our understanding of the role of HH/GLI signaling in pancreatic cancer.
项目总结/文摘

项目成果

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Benjamin Allen其他文献

Benjamin Allen的其他文献

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{{ truncateString('Benjamin Allen', 18)}}的其他基金

Kinesin-2 Regulation of GLI Function in Hedgehog Signal Transduction
Kinesin-2 对 Hedgehog 信号转导中 GLI 功能的调节
  • 批准号:
    9441784
  • 财政年份:
    2016
  • 资助金额:
    $ 59.12万
  • 项目类别:
Kinesin-2 Regulation of GLI Function in Hedgehog Signal Transduction
Kinesin-2 对 Hedgehog 信号转导中 GLI 功能的调节
  • 批准号:
    9274992
  • 财政年份:
    2016
  • 资助金额:
    $ 59.12万
  • 项目类别:
Dosage-Dependent Hedgehog Signaling in Pancreatic Cancer
胰腺癌中剂量依赖性 Hedgehog 信号转导
  • 批准号:
    9762017
  • 财政年份:
    2015
  • 资助金额:
    $ 59.12万
  • 项目类别:
Dosage-Dependent Hedgehog Signaling in Pancreatic Cancer
胰腺癌中剂量依赖性 Hedgehog 信号转导
  • 批准号:
    9150517
  • 财政年份:
    2015
  • 资助金额:
    $ 59.12万
  • 项目类别:
Dosage-Dependent Hedgehog Signaling in Pancreatic Cancer
胰腺癌中剂量依赖性 Hedgehog 信号转导
  • 批准号:
    9328035
  • 财政年份:
    2015
  • 资助金额:
    $ 59.12万
  • 项目类别:
Hedgehog signaling in maintaining taste organ structure and function: basic and clinical studies
Hedgehog信号传导在维持味觉器官结构和功能中的作用:基础和临床研究
  • 批准号:
    8841584
  • 财政年份:
    2014
  • 资助金额:
    $ 59.12万
  • 项目类别:
Hedgehog signaling in maintaining taste organ structure and function: basic and clinical studies
Hedgehog信号传导在维持味觉器官结构和功能中的作用:基础和临床研究
  • 批准号:
    9171921
  • 财政年份:
    2014
  • 资助金额:
    $ 59.12万
  • 项目类别:
Novel Hedgehog Receptors As Therapeutic Targets In Pancreatic Cancer
新型 Hedgehog 受体作为胰腺癌的治疗靶点
  • 批准号:
    8449102
  • 财政年份:
    2012
  • 资助金额:
    $ 59.12万
  • 项目类别:
Novel Hedgehog Receptors As Therapeutic Targets In Pancreatic Cancer
新型 Hedgehog 受体作为胰腺癌的治疗靶点
  • 批准号:
    8285346
  • 财政年份:
    2012
  • 资助金额:
    $ 59.12万
  • 项目类别:
University of Michigan Postbaccalaureate Research Education Program (UM PREP)
密歇根大学学士后研究教育计划(UM PREP)
  • 批准号:
    10581633
  • 财政年份:
    2009
  • 资助金额:
    $ 59.12万
  • 项目类别:

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非洲人群中 HIV 氨基酸变异与 CHD1L 和 HLA I 类基因座的保护性宿主等位基因的关联
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