Targeting extracellular matrix-cancer stem cell interactions in pancreatic cancer

靶向胰腺癌中细胞外基质-癌症干细胞的相互作用

基本信息

  • 批准号:
    9270517
  • 负责人:
  • 金额:
    $ 37.06万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2016
  • 资助国家:
    美国
  • 起止时间:
    2016-05-06 至 2021-04-30
  • 项目状态:
    已结题

项目摘要

 DESCRIPTION (provided by applicant): Pancreatic cancer continues to have one of the highest mortality rates of any malignancy and the 5-year survival rate remains less than 5% largely because of its propensity for metastasis and drug resistance. These problems have not yet been overcome, but recent research indicates that there is great variability in the intrinsic potential among distinct subpopulations of tumor cells to metastasize or resist treatment; that pancreatic cancer cells are functionally heterogeneous. We and others identified several phenotypically distinct pancreatic cancer cell populations that are enriched in tumor-initiating capacity, defining them as cancer stem cells (CSCs). The aldehyde dehydrogenase (ALDH)-expressing CSC population is associated with worse clinical outcomes, resistant to chemotherapy, and has higher metastatic potential. The mechanisms that regulate the functional characteristics of CSCs as well as what regulates the balance between pancreatic CSCs and non-CSCs are poorly understood. Our recent research indicates that pancreatic CSCs are maintained by direct interactions with certain proteins in the tumor microenvironment (TME) and focal adhesion kinase (FAK) signaling. We hypothesize that the TME plays a critical role in regulating the equilibrium between CSCs and non-CSCs, and that specific signaling pathways activated by the TME regulate CSC functional characteristics. Using our groups' expertise we propose to: 1) Determine the role of specific extracellular matrix proteins and integrins on FAK activation and regulation of the equilibrium between CSC and non-CSCs, 2) Evaluate the role of FAK activation on tumor progression and CSC function in the genetically engineered Ptf1a-Cre; KrasG12D/+; p53R172H/+ (KPC) pancreatic cancer mouse model, 3) Determine the most effective clinical setting in which antagonists of FAK can inhibit pancreatic cancer growth and metastasis using in vivo models, and 4) Evaluate if FAK protein expression can predict response to therapy. These studies will enhance our understanding of mechanistic interactions with the TME that regulate pancreatic CSCs, and will guide the clinical development of novel CSC-directed therapies.
 描述(由申请人提供):胰腺癌仍然是所有恶性肿瘤中死亡率最高的肿瘤之一,5年生存率仍然低于5%,主要是因为其转移和耐药性的倾向。这些问题尚未被克服,但最近的研究表明,在不同的肿瘤细胞亚群之间转移或抵抗治疗的内在潜力存在很大的差异;胰腺癌细胞在功能上是异质的。我们和其他人鉴定了几种表型不同的胰腺癌细胞群,这些细胞群富含肿瘤起始能力,将其定义为癌症干细胞(CSC)。表达乙醛脱氢酶(ALDH)的CSC人群与更差的临床结局、化疗耐药和更高的转移潜力相关。调节CSC的功能特征的机制以及调节胰腺CSC和非CSC之间的平衡的机制知之甚少。我们最近的研究表明,胰腺CSC是通过与肿瘤微环境(TME)中的某些蛋白质和粘着斑激酶(FAK)信号直接相互作用来维持的。我们假设TME在调节CSC和非CSC之间的平衡中起着关键作用,并且由TME激活的特定信号通路调节CSC的功能特征。利用我们小组的专业知识,我们提出:1)确定特定的细胞外基质蛋白和整合素对FAK活化和CSC与非CSC之间平衡的调节的作用,2)评估FAK活化对肿瘤进展和基因工程Ptf 1a-Cre; KrasG 12 D/+中CSC功能的作用; p53 R172 H/+(KPC)胰腺癌小鼠模型,3)使用体内模型确定FAK拮抗剂可抑制胰腺癌生长和转移的最有效临床环境,和4)评估FAK蛋白表达是否可预测对治疗的响应。这些研究将增强我们对调节胰腺CSC的TME的机制相互作用的理解,并将指导新型CSC导向疗法的临床开发。

项目成果

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WILLIAM H MATSUI其他文献

WILLIAM H MATSUI的其他文献

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{{ truncateString('WILLIAM H MATSUI', 18)}}的其他基金

MENTORING AND RESEARCH IN CANCER STEM CELLS
癌症干细胞的指导和研究
  • 批准号:
    9922873
  • 财政年份:
    2016
  • 资助金额:
    $ 37.06万
  • 项目类别:
Proteostasis and stem cell aging
蛋白质稳态和干细胞衰老
  • 批准号:
    9127068
  • 财政年份:
    2015
  • 资助金额:
    $ 37.06万
  • 项目类别:
Myeloma stem cell targeting by liver x receptors
肝脏 x 受体靶向骨髓瘤干细胞
  • 批准号:
    8189635
  • 财政年份:
    2011
  • 资助金额:
    $ 37.06万
  • 项目类别:
Cellular diversity and clinical relevance of stem cells in pancreatic cancer
胰腺癌干细胞的细胞多样性和临床相关性
  • 批准号:
    8890794
  • 财政年份:
    2011
  • 资助金额:
    $ 37.06万
  • 项目类别:
Cellular diversity and clinical relevance of stem cells in pancreatic cancer
胰腺癌干细胞的细胞多样性和临床相关性
  • 批准号:
    8184166
  • 财政年份:
    2011
  • 资助金额:
    $ 37.06万
  • 项目类别:
Cellular diversity and clinical relevance of stem cells in pancreatic cancer
胰腺癌干细胞的细胞多样性和临床相关性
  • 批准号:
    8332790
  • 财政年份:
    2011
  • 资助金额:
    $ 37.06万
  • 项目类别:
Myeloma stem cell targeting by liver x receptors
肝脏 x 受体靶向骨髓瘤干细胞
  • 批准号:
    8294563
  • 财政年份:
    2011
  • 资助金额:
    $ 37.06万
  • 项目类别:
Cellular diversity and clinical relevance of stem cells in pancreatic cancer
胰腺癌干细胞的细胞多样性和临床相关性
  • 批准号:
    8504982
  • 财政年份:
    2011
  • 资助金额:
    $ 37.06万
  • 项目类别:
Cancer Stem Cell Targeting in Multiple Myeloma
多发性骨髓瘤中的癌症干细胞靶向
  • 批准号:
    8016077
  • 财政年份:
    2008
  • 资助金额:
    $ 37.06万
  • 项目类别:
Cancer Stem Cell Targeting in Multiple Myeloma
多发性骨髓瘤中的癌症干细胞靶向
  • 批准号:
    7588870
  • 财政年份:
    2008
  • 资助金额:
    $ 37.06万
  • 项目类别:

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