Deciphering molecular mechanisms underlying cellular plasticity and metastasis

破译细胞可塑性和转移的分子机制

基本信息

  • 批准号:
    10228753
  • 负责人:
  • 金额:
    $ 3.67万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2020
  • 资助国家:
    美国
  • 起止时间:
    2020-08-04 至 2021-11-30
  • 项目状态:
    已结题

项目摘要

Project Summary/Abstract Cellular plasticity, a feature associated with epithelial-to-mesenchymal transition (EMT), contributes to tumor cell survival, migration, invasion, and therapy resistance. Across human cancer, tumors that are high grade, poorly differentiated, and have undergone EMT carry a worse prognosis with a high likelihood of metastasizing to distant organs. EMT is a common feature associated with tumor progression and is thought to be critical to cancer cell dissemination in some tumors, such as pancreatic ductal adenocarcinoma (PDA). PDA is a lethal and poorly understood human malignancy that is characterized by an activating mutation in KRAS. Additionally, AXL, a receptor tyrosine kinase (RTK), has been implicated in tumor progression, metastasis, therapy resistance, and EMT in multiple cancer types including PDA. During my dissertation studies, I have found that TANK-binding kinase 1 (TBK1), a critical downstream effector of mutant active KRAS, is central to AXL-driven EMT in KRAS-mutant PDA. However, the mechanism of how TBK1 drives EMT has yet to be elucidated. We hypothesize that TBK1 drives EMT via activation of AKT3 and the stability of downstream transcriptional networks. My data demonstrate that AKT3 is activated downstream of TBK1 in response to stimulation of AXL, which leads to the binding of AKT3 and Slug in an AXL-TBK1 dependent manner. To complete my dissertation, I will establish the function of AKT3 in driving EMT downstream of Axl and TBK1 with the following goals: 1) Establish the necessity of AKT3 for Axl and TBK1 driven EMT; 2) Evaluate EMT transcription factors engaged downstream of TBK1 and 3) Determine the effect of AKT3 activation on the stability of EMT transcription factors. Despite significant evidence that EMT directly contributes to tumor progression, several studies have suggested EMT is not required for the metastatic spread of PDA and breast cancer. For example, most metastatic lesions are known to exhibit epithelial features, an observation that seems to be at odds with EMT as a prerequisite for metastasis. As such, the importance of EMT in cancer biology h as been questioned. I hypothesize that the chronic activation of an EMT program within a tumor may depend on paracrine signals within the tumor microenvironment, dictating whether the tumor cells undergo EMT or MET. Because these cells exist in a plastic state, it is possible that these tumor cells readily revert their phenotype based on a microenvironment-specific context and factors. Additionally, current in vivo lineage- tracing technology has not settled the debate between the importance of collective m igration and/or EMT for metastatic dissemination. During my postdoctoral research, I aim to investigate the role of EMT in metastasis using in vivo lineage tracing, single-cell sequencing, and organoids to better understand epithelial plasticity in an oncogene- and tissue-specific manner. Understanding this process will aid in the development of effective metastatic cancer therapies and will direct future research directions in metastasis.
项目总结/摘要 细胞可塑性,与上皮细胞间质转化(EMT)相关的特征,有助于 肿瘤细胞存活、迁移、侵袭和治疗抗性。在人类癌症中, 分级、分化差、经历过EMT的患者预后较差, 转移到远处器官。EMT是与肿瘤进展相关的常见特征, 在某些肿瘤中,如胰腺导管腺癌, (PDA)。动脉导管未闭是一种致死性的人类恶性肿瘤, KRAS突变此外,受体酪氨酸激酶(RTK)AXL与肿瘤的发生、发展和预后密切相关。 包括PDA在内的多种癌症类型中的进展、转移、耐药性和EMT。在我 在论文研究中,我发现TANK结合激酶1(TBK 1),一个关键的下游效应子, 突变的活性KRAS是KRAS突变的PDA中AXL驱动的EMT的核心。然而, TBK 1驱动EMT尚未阐明。我们假设TBK 1通过激活AKT 3驱动EMT 和下游转录网络的稳定性。我的数据显示AKT 3被激活了 在TBK 1的下游响应于AXL的刺激,这导致AKT 3和Slug的结合, AXL-TBK 1依赖性方式。为了完成我的论文,我将建立AKT 3在驾驶EMT中的功能 1)确定AKT 3对于Axl和TBKl驱动的AKT 3的必要性, EMT; 2)评估TBK 1下游参与的EMT转录因子和3)确定AKT 3的作用 激活对EMT转录因子稳定性的影响。 尽管有大量证据表明EMT直接导致肿瘤进展,但一些研究表明, 提示PDA和乳腺癌的转移扩散不需要EMT。比如多数 已知转移性病变表现出上皮特征,这一观察结果似乎与 EMT是转移的先决条件。因此,EMT在癌症生物学中的重要性已经被 质疑我假设肿瘤内EMT程序的慢性激活可能取决于 肿瘤微环境内的旁分泌信号,决定肿瘤细胞是否经历EMT或 MET.因为这些细胞以可塑状态存在,所以这些肿瘤细胞很容易逆转其 表型基于微环境特定的背景和因素。此外,目前的体内谱系- 追踪技术还没有解决集体移民和/或EMT的重要性之间的争论 用于转移性传播。在我的博士后研究期间,我的目标是调查EMT在以下方面的作用: 使用体内谱系追踪,单细胞测序和类器官来更好地了解转移 癌基因和组织特异性方式的上皮可塑性。了解这个过程将有助于 发展有效的转移性癌症治疗,并将指导未来的研究方向转移。

项目成果

期刊论文数量(5)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
AXL Inhibitor TP-0903 Reduces Metastasis and Therapy Resistance in Pancreatic Cancer.
  • DOI:
    10.1158/1535-7163.mct-21-0293
  • 发表时间:
    2022-01
  • 期刊:
  • 影响因子:
    5.7
  • 作者:
    Zhang Y;Arner EN;Rizvi A;Toombs JE;Huang H;Warner SL;Foulks JM;Brekken RA
  • 通讯作者:
    Brekken RA
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Emily Nicole Arner其他文献

Emily Nicole Arner的其他文献

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{{ truncateString('Emily Nicole Arner', 18)}}的其他基金

Deciphering molecular mechanisms of Epithelial Plasticity
解读上皮可塑性的分子机制
  • 批准号:
    10533831
  • 财政年份:
    2021
  • 资助金额:
    $ 3.67万
  • 项目类别:
Deciphering molecular mechanisms of Epithelial Plasticity
解读上皮可塑性的分子机制
  • 批准号:
    10523132
  • 财政年份:
    2021
  • 资助金额:
    $ 3.67万
  • 项目类别:
Deciphering molecular mechanisms underlying cellular plasticity and metastasis
破译细胞可塑性和转移的分子机制
  • 批准号:
    10064939
  • 财政年份:
    2020
  • 资助金额:
    $ 3.67万
  • 项目类别:

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