Influence of hemodynamic shear stress on circulating tumor cells

血流动力学剪切应力对循环肿瘤细胞的影响

基本信息

  • 批准号:
    10573281
  • 负责人:
  • 金额:
    $ 35.91万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2022
  • 资助国家:
    美国
  • 起止时间:
    2022-02-15 至 2027-01-31
  • 项目状态:
    未结题

项目摘要

Circulating tumor cells (CTCs) are exposed to various insults thought to reduce their survival including lack of anchorage and trophic support from the primary tumor microenvironment, immune-mediated destruction and exposure to hemodynamic forces that may mechanically destroy them. However, the relative contribution of these factors to CTC survival and their overall role in metastasis is unclear. It has recently been shown that cancer cells from many tissue origins actively resist destruction by fluid shear stress (FSS), implying that viable CTCs are not mechanically fragile as suspected. Our long-term goal is to understand the biomechanical influences on CTCs and how this contributes to metastasis. The objective of this proposal is to determine the mechanism of FSS resistance in cancer cells and its role in metastatic colonization. Our central hypothesis is that mechano-adaptation of viable CTCs to FSS promotes their survival in the circulation and “primes” them for subsequent events in metastasis. Our hypothesis is based on our previously published and preliminary data presented below as well as recently published data from others which is supportive of our hypothesis. The rationale for the proposed research is that once we understand the mechanism underlying FSS resistance; this would represent a novel therapeutic approach aimed at decreasing the survival of CTCs by enhancing their destruction due to the mechanical forces that naturally exist in the circulation. Guided by preliminary data, the central hypothesis will be tested by pursuing the following specific aims: 1) Define molecular mechanisms of FSS resistance; 2) Determine the effect of FSS exposure on metastatic colonization; 3) Determine the effectiveness of inhibiting FSS resistance as an anti-metastatic strategy. To accomplish these aims, we will employ a forward genetic screen to identify novel genes that mediate FSS resistance and determine their involvement with RhoA- actomyosin interactions. Short-term survival of CTCs will be assessed using a novel mouse model to measure entrapment of intact CTCs in the lung and destruction of CTCs measured by a plasma biomarker. We will validate novel genes identified in a forward genetic screen in similar assays. We will determine the involvement of RhoA- YAP activation by FSS in supporting the survival and extravasation of cancer cells lodged in the microcirculation. Finally, we will test the potential of clinically actionable drugs that sensitize cells to FSS as well as conditional RhoA/YAP knockdown to block productive metastatic colonization in mouse models. The proposed research is innovative because, it represents a paradigm shift from the idea that CTCs are mechanically fragile by elucidating a mechanism whereby viable CTCs actively resist destruction by hemodynamic forces and drives further events in metastasis. The proposed research is significant because defining the mechanisms and consequences of FSS resistance in CTCs will open entirely new diagnostic and therapeutic possibilities in cancer patients.
循环中的肿瘤细胞(CTCs)暴露在各种侮辱中,被认为会降低它们的存活率,包括缺乏 来自原发肿瘤微环境的锚定和营养支持,免疫介导的破坏和 暴露在可能机械地摧毁他们的血液动力学力量中。然而,相对的贡献是 这些因素对CTC的生存及其在转移中的整体作用尚不清楚。最近有证据表明, 来自许多组织来源的癌细胞积极抵抗流体剪应力(FSS)的破坏,这意味着 CTC在机械上并不像人们所怀疑的那样脆弱。我们的长期目标是了解生物力学 对CTCs的影响以及这种影响如何促进转移。这项建议的目标是确定 癌细胞对FSS耐药的机制及其在转移定植中的作用。我们的中心假设是 有活力的CTC对FSS的机械适应促进了它们在循环中的生存,并为它们提供了 转移中的后续事件。我们的假设是基于我们之前发表的初步数据 下面给出的数据以及其他人最近发布的数据支持了我们的假设。这个 这项拟议研究的基本原理是,一旦我们了解了FSS抵抗的机制;这 将代表一种新的治疗方法,旨在通过增强CTC的存活率来降低CTC的存活率 由于循环中自然存在的机械力造成的破坏。在初步数据的指引下, 中心假说将通过追求以下具体目标来检验:1)确定FSS的分子机制 抗性;2)确定FSS暴露对转移定植的影响;3)确定有效性 将抑制FSS耐药作为抗转移策略。为了实现这些目标,我们将雇佣一名前锋 基因筛选以确定介导FSS抗性的新基因并确定它们与RhoA- 肌动球蛋白相互作用。将使用一种新的小鼠模型来评估CTC的短期存活率 通过血浆生物标记物测量完整CTCs在肺内的滞留和CTCs的破坏。我们将验证 在类似的分析中,在正向遗传筛查中发现了新的基因。我们将确定RhoA的参与- 通过FSS激活YAP,支持滞留在微循环中的癌细胞存活和渗出。 最后,我们将测试临床上可操作的药物的潜力,这些药物使细胞对FSS敏感,以及条件 RhoA/YAP基因敲除以阻断小鼠模型中的生产性转移定植。拟议的研究是 创新是因为,它代表了一种范式的转变,通过阐明CTC是机械脆弱的 有活力的CTC主动抵抗血液动力学力量的破坏并推动进一步事件发生的机制 在转移中。拟议的研究具有重要意义,因为定义了FSS的机制和后果 CTCs的耐药性将为癌症患者的诊断和治疗带来全新的可能性。

项目成果

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Michael D Henry其他文献

Michael D Henry的其他文献

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{{ truncateString('Michael D Henry', 18)}}的其他基金

Influence of hemodynamic shear stress on circulating tumor cells
血流动力学剪切应力对循环肿瘤细胞的影响
  • 批准号:
    10442218
  • 财政年份:
    2022
  • 资助金额:
    $ 35.91万
  • 项目类别:
Improved detection of bladder cancer recurrence using a biophysical biomarker
使用生物物理生物标志物改进膀胱癌复发的检测
  • 批准号:
    9988591
  • 财政年份:
    2017
  • 资助金额:
    $ 35.91万
  • 项目类别:
Effects of fluid shear stress on circulating tumor cells
流体剪切应力对循环肿瘤细胞的影响
  • 批准号:
    9111247
  • 财政年份:
    2016
  • 资助金额:
    $ 35.91万
  • 项目类别:
(PQC2) Resistance to fluid shear stress: a novel biomarker of cancer cells
(PQC2) 对流体剪切应力的抵抗力:癌细胞的新型生物标志物
  • 批准号:
    8589754
  • 财政年份:
    2013
  • 资助金额:
    $ 35.91万
  • 项目类别:
(PQC2) Resistance to fluid shear stress: a novel biomarker of cancer cells
(PQC2) 对流体剪切应力的抵抗力:癌细胞的新型生物标志物
  • 批准号:
    8721904
  • 财政年份:
    2013
  • 资助金额:
    $ 35.91万
  • 项目类别:
Effects of pesticides on prostate cancer progression in PTEN mutant mice
农药对 PTEN 突变小鼠前列腺癌进展的影响
  • 批准号:
    7938731
  • 财政年份:
    2009
  • 资助金额:
    $ 35.91万
  • 项目类别:
Effects of pesticides on prostate cancer progression in PTEN mutant mice
农药对 PTEN 突变小鼠前列腺癌进展的影响
  • 批准号:
    7814051
  • 财政年份:
    2009
  • 资助金额:
    $ 35.91万
  • 项目类别:
Role of Dystroglycan in Prostate Cancer Progression
肌营养不良聚糖在前列腺癌进展中的作用
  • 批准号:
    7655510
  • 财政年份:
    2008
  • 资助金额:
    $ 35.91万
  • 项目类别:
Mouse model of obesity and prostate cancer progression.
肥胖和前列腺癌进展的小鼠模型。
  • 批准号:
    7742984
  • 财政年份:
    2008
  • 资助金额:
    $ 35.91万
  • 项目类别:
Role of Dystroglycan in Prostate Cancer Progression
肌营养不良聚糖在前列腺癌进展中的作用
  • 批准号:
    8071515
  • 财政年份:
    2008
  • 资助金额:
    $ 35.91万
  • 项目类别:

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