(PQC2) Localization as a determinant of cancer dormancy

(PQC2) 定位作为癌症休眠的决定因素

基本信息

  • 批准号:
    8876904
  • 负责人:
  • 金额:
    $ 54.7万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2015
  • 资助国家:
    美国
  • 起止时间:
    2015-05-18 至 2019-04-30
  • 项目状态:
    已结题

项目摘要

 DESCRIPTION (provided by applicant): This proposal aims to address the provocative question PQC- 2: What molecular or cellular events establish tumor dormancy after treatment and what leads to recurrence? We will address this question by examining the bone marrow (BM), a location known to provide a favorable microenvironment not only for hematologic malignancies, but also for solid tumor cells that frequently seed and persist in this location. These cells can reemerge after prolonged periods of apparent inactivity and become the source of new cancer growth. Understanding how dormancy is regulated is important for developing therapeutic strategies that aim to prevent cancer relapse. Our central hypothesis is that localization is an important determinant of dormancy. Localization of normal hematopoietic stem cells (HSCs) to proper niches in the BM is critical for maintaining quiescence and long-term function of the HSC. Here we propose to investigate the relationship between dormancy and localization of malignant cells in the BM following chemotherapy. We hypothesize that dormancy is maintained by localization of malignant cells in quiescent niches, and subsequent events that alter their localization can trigger the malignant cells to exit their quiescent state. By tracking individual cancer cells expressing a novel cell cycle fluorescent indicator in the mouse BM using intravital microscopy, we will identify the location of quiescent niches where cells are maintained in the G0 state. We will examine the link between quiescence and hypoxia by mapping local oxygen concentration in the BM with high spatial resolution using two-photon phosphorescence lifetime microscopy (2PLM), and identify niche-specific molecular expression by laser microdissection and capturing of niche cells for RNA-seq. Finally, we will examine if genetic or pharmacologic manipulations of the niche components can result in altered cellular localization, changes in cell cycle status, and susceptibility to chemotherapy. If successful, this work can lead to a new way of sensitizing cancer cells to chemotherapy by targeting their localization.
 描述(由申请人提供):该提案旨在解决 PQC-2 这一具有争议性的问题:哪些分子或细胞事件在治疗后建立肿瘤休眠以及哪些导致复发?我们将通过检查骨髓 (BM) 来解决这个问题,众所周知,骨髓 (BM) 不仅为血液恶性肿瘤提供有利的微环境,而且还为经常在该位置播种和持续存在的实体瘤细胞提供有利的微环境。这些细胞在长时间明显不活动后可以重新出现,并成为新的癌症生长的来源。了解休眠是如何调节的对于制定旨在预防癌症复发的治疗策略非常重要。我们的中心假设是定位是休眠的重要决定因素。正常造血干细胞 (HSC) 定位到 BM 中的适当位置对于维持 HSC 的静止和长期功能至关重要。在这里,我们建议研究化疗后骨髓中恶性细胞的休眠与定位之间的关系。我们假设休眠是通过将恶性细胞定位在静止状态来维持的,并且随后改变其​​定位的事件可以触发恶性细胞退出其静止状态。通过追踪 使用活体显微镜在小鼠骨髓中表达新型细胞周期荧光指示剂的单个癌细胞,我们将确定细胞维持的静止生态位的位置 处于G0状态。我们将通过使用双光子磷光寿命显微镜 (2PLM) 以高空间分辨率绘制 BM 中的局部氧浓度来检查静止和缺氧之间的联系,并通过激光显微切割和捕获小生境细胞进行 RNA 测序来识别小生境特异性分子表达。最后,我们将检查利基成分的遗传或药理学操作是否会导致细胞定位的改变、细胞周期状态的变化以及对化疗的敏感性的改变。如果成功,这项工作可以带来一种通过靶向癌细胞定位来使癌细胞对化疗敏感的新方法。

项目成果

期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)

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Charles P. Lin其他文献

Deep tissue single cell MSC ablation using a fiber laser source to evaluate therapeutic potential in osteogenesis imperfecta
使用光纤激光源进行深部组织单细胞 MSC 消融评估成骨不全症的治疗潜力
  • DOI:
    10.1117/12.2213292
  • 发表时间:
    2016
  • 期刊:
  • 影响因子:
    4.3
  • 作者:
    K. Tehrani;Emily G Pendleton;Charles P. Lin;L. Mortensen
  • 通讯作者:
    L. Mortensen
Haematopoietic stem cells depend on Gαs-mediated signalling to engraft bone marrow
造血干细胞依赖于 Gαs 介导的信号传导来植入骨髓
  • DOI:
    10.1038/nature07859
  • 发表时间:
    2009-03-25
  • 期刊:
  • 影响因子:
    48.500
  • 作者:
    Gregor B. Adams;Ian R. Alley;Ung-il Chung;Karissa T. Chabner;Nathaniel T. Jeanson;Cristina Lo Celso;Emily S. Marsters;Min Chen;Lee S. Weinstein;Charles P. Lin;Henry M. Kronenberg;David T. Scadden
  • 通讯作者:
    David T. Scadden
A Sensorless Adaptive Optics Scanning Laser Ophthalmoscope for Mice
用于小鼠的无传感器自适应光学扫描激光检眼镜
  • DOI:
  • 发表时间:
    2006
  • 期刊:
  • 影响因子:
    0
  • 作者:
    D. Biss;R. Webb;Yaopeng Zhou;T. Bifano;Charles P. Lin
  • 通讯作者:
    Charles P. Lin
Computational modeling of stress transient and bubble evolution in short-pulse laser-irradiated melanosome particles
短脉冲激光照射黑素体颗粒中应力瞬态和气泡演化的计算模型
  • DOI:
  • 发表时间:
    1997
  • 期刊:
  • 影响因子:
    0
  • 作者:
    M. Strauss;P. Amendt;R. London;D. Maitland;M. Glinsky;Charles P. Lin;Michael W. Kelly
  • 通讯作者:
    Michael W. Kelly
Declined presentation inflammatory modulation of hematopoietic stromal niche cells by TNF-α leads to rapid mobilization of hematopoietic stem/progenitor cells (HSPC) and neutrophils
  • DOI:
    10.1016/j.exphem.2015.06.134
  • 发表时间:
    2015-09-01
  • 期刊:
  • 影响因子:
  • 作者:
    Shin-Young Park;Eun Young Anna Han;Yookyung Jung;Charles P. Lin;Leslie E. Silberstein
  • 通讯作者:
    Leslie E. Silberstein

Charles P. Lin的其他文献

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{{ truncateString('Charles P. Lin', 18)}}的其他基金

Local Skull Marrow Sensing and Response to CNS Inflammation
局部颅骨对中枢神经系统炎症的感知和反应
  • 批准号:
    10654045
  • 财政年份:
    2022
  • 资助金额:
    $ 54.7万
  • 项目类别:
Core 1: Cellular diagnostics/imaging core
核心1:细胞诊断/成像核心
  • 批准号:
    10670739
  • 财政年份:
    2019
  • 资助金额:
    $ 54.7万
  • 项目类别:
Core 1: Cellular diagnostics/imaging core
核心1:细胞诊断/成像核心
  • 批准号:
    10469358
  • 财政年份:
    2019
  • 资助金额:
    $ 54.7万
  • 项目类别:
Core 1: Cellular diagnostics/imaging core
核心1:细胞诊断/成像核心
  • 批准号:
    10238046
  • 财政年份:
    2019
  • 资助金额:
    $ 54.7万
  • 项目类别:
Live Imaging of Intact Airway
完整气道的实时成像
  • 批准号:
    10240652
  • 财政年份:
    2018
  • 资助金额:
    $ 54.7万
  • 项目类别:
(PQC2) Localization as a determinant of cancer dormancy
(PQC2) 定位作为癌症休眠的决定因素
  • 批准号:
    9262173
  • 财政年份:
    2015
  • 资助金额:
    $ 54.7万
  • 项目类别:
Multi-wavelength femtosecond laser sources for intravital multiphoton microscopy
用于活体多光子显微镜的多波长飞秒激光源
  • 批准号:
    8562082
  • 财政年份:
    2013
  • 资助金额:
    $ 54.7万
  • 项目类别:
Multi-wavelength femtosecond laser sources for intravital multiphoton microscopy
用于活体多光子显微镜的多波长飞秒激光源
  • 批准号:
    8852123
  • 财政年份:
    2013
  • 资助金额:
    $ 54.7万
  • 项目类别:
Multi-wavelength femtosecond laser sources for intravital multiphoton microscopy
用于活体多光子显微镜的多波长飞秒激光源
  • 批准号:
    9087255
  • 财政年份:
    2013
  • 资助金额:
    $ 54.7万
  • 项目类别:
Multi-wavelength femtosecond laser sources for intravital multiphoton microscopy
用于活体多光子显微镜的多波长飞秒激光源
  • 批准号:
    8701293
  • 财政年份:
    2013
  • 资助金额:
    $ 54.7万
  • 项目类别:

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急性粒细胞白血病白血病干细胞动力学的计算分析
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  • 批准号:
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  • 财政年份:
    1980
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