Defining the role of type III collagen and the collagen-binding receptor DDR1 in metastatic dormancy

定义 III 型胶原和胶原结合受体 DDR1 在转移休眠中的作用

基本信息

项目摘要

Project Summary/Abstract Background: Metastasis is the primary cause of death of cancer patients. Disseminated tumor cells (DTCs) leave the primary tumor and seed target organs originating metastasis, years or decades after treatment. This delay in growth is mediated by a process called tumor dormancy. The extracellular matrix (ECM)-tumor cell interactions have been shown to regulate the hallmark of cancer; from primary tumor growth to migration, invasion and metastasis. However, how ECM sensing and remodeling can induce and sustain dormancy of DTCs is unclear. Moreover, whether DTCs assemble dormancy-supportive ECM niches to sustain their phenotype is also an unanswered question. We will explore the hypothesis that ECM remodeling by dormant cells contribute to tumor dormancy by constructing a dormant ECM niche rich in collagen III (COL III). Hypothesis: Our overall hypothesis states that dormant cancer cells can construct their own “dormancy- supportive niche” by remodeling and depositing a COL III rich ECM that sustain their phenotype. Objective: The overall goal of this project is two-fold: 1) to understand the role of the COL III ECM on the formation of dormancy-supportive niches and 2) to determine how the interaction with the collagen III ECM through DDR1 regulates the dormancy-to-reactivation transition. Specific Aims: #1: To determine how fibrillar collagen III networks contribute to establish a dormancy-supportive niche. #2: To identify the molecular mechanisms through which collagen receptor DDR1 modulates assembly of a pro-quiescence ECM. Study design/Methods: 1) The approaches available to study the biology of dormant cells in real-time in vivo are limited. We propose to use high-resolution imaging tools combined with dormancy models to study tumor cell-ECM interactions during dormancy. We have been developing an imaging approach that includes: i) Multiphoton imaging and second harmonic generation (SHG) and ii) activity reporters for dormancy-related specific pathways to measure changes in p38/ERK signaling and cell cycle status during dormancy. 2) To analyze the ECM composition and remodeling we use quantitative proteomics in collaboration with Dr. Naba. Relevance: This project is innovative both at the conceptual and at the methodological level. We propose to study the following aspects of metastasis: 1) how DTCs create a dormant ECM niche enriched in COL III to sustain dormancy; 2) the role of COL III/DDR1 interaction in regulating dormancy; 3) how IFNg/STAT1 signaling regulates tumor dormancy through ECM remodeling; 4) how disruption of a pro-quiescence ECM proteome and increase in LTBP1 mediate dormancy-to-reactivation transition. We expect our studies to have a significant impact on biomedicine because they will uncover the mechanisms regulating dormant cell-ECM interactions, which will be an efficient way of identifying targets to prevent metastasis.
项目总结/摘要 背景:转移是癌症患者死亡的主要原因。播散性肿瘤细胞(DTC) 在治疗后数年或数十年,留下原发性肿瘤和起源转移的种子靶器官。这 生长的延迟是由一种称为肿瘤休眠的过程介导的。细胞外基质(ECM)-肿瘤细胞 已经显示相互作用调节癌症的标志;从原发性肿瘤生长到迁移, 侵袭和转移。然而,如何ECM传感和重塑可以诱导和维持休眠, DTC不清楚。此外,DTC是否组装支持休眠的ECM小生境以维持其 表型也是一个没有答案的问题。我们将探讨这一假设,即ECM重塑由休眠 细胞通过构建富含胶原蛋白III(COL III)的休眠ECM小生境而有助于肿瘤休眠。 假设:我们的总体假设指出,休眠的癌细胞可以构建自己的“休眠- 通过重塑和沉积维持其表型的富含COL III的ECM来形成“支持性小生境”。 目的:本项目的总体目标有两个方面:1)了解COL III ECM在 形成休眠支持小生境和2)确定如何与胶原III ECM相互作用 通过DDR 1调节休眠到再激活的过渡。 具体目的:#1:确定纤维状胶原蛋白III网络如何有助于建立睡眠支持性 利基#2:为了确定胶原蛋白受体DDR 1调节胶原蛋白组装的分子机制, 一个预静止ECM 研究设计/方法:1)可用于在体内实时研究休眠细胞生物学的方法 是有限的。我们建议使用高分辨率成像工具结合休眠模型来研究肿瘤 细胞与ECM的相互作用。我们一直在开发一种成像方法,包括:i) 多光子成像和二次谐波产生(SHG)和ii)休眠相关的活性报告物 特异性途径来测量休眠期间p38/ERK信号传导和细胞周期状态的变化。2)到 我们与Naba博士合作使用定量蛋白质组学分析ECM组成和重塑。 相关性:该项目在概念和方法上都具有创新性。我们建议 研究转移的以下方面:1)DTC如何创建富含COL III的休眠ECM小生境, 维持休眠; 2)COL III/DDR 1相互作用在调节休眠中的作用; 3)IFNg/STAT 1信号传导如何 通过ECM重塑调节肿瘤休眠; 4)如何破坏前静止ECM蛋白质组, LTBP 1增加介导休眠到再激活的转变。我们希望我们的研究能对 对生物医学的影响,因为他们将揭示调节休眠细胞-ECM相互作用的机制, 这将是鉴定靶点以防止转移的有效方式。

项目成果

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Jose Javier Bravo-Cordero其他文献

Jose Javier Bravo-Cordero的其他文献

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{{ truncateString('Jose Javier Bravo-Cordero', 18)}}的其他基金

IMAT-ITCR Collaboration: Artificial intelligence enhanced breast cancer dormancy cell classification-based organelle-morphology and topology
IMAT-ITCR 合作:人工智能增强乳腺癌休眠细胞分类的细胞器形态和拓扑
  • 批准号:
    10884760
  • 财政年份:
    2023
  • 资助金额:
    $ 38.77万
  • 项目类别:
Intersectional genetics-based biosensors for dormant cancer cells
基于交叉遗传学的休眠癌细胞生物传感器
  • 批准号:
    10612300
  • 财政年份:
    2023
  • 资助金额:
    $ 38.77万
  • 项目类别:
Recording the natural history of cancer progression using a Crainbow model of HER2+ cancer
使用 HER2 癌症的 Crainbow 模型记录癌症进展的自然史
  • 批准号:
    10630320
  • 财政年份:
    2022
  • 资助金额:
    $ 38.77万
  • 项目类别:
Recording the natural history of cancer progression using a Crainbow model of HER2+ cancer
使用 HER2 癌症的 Crainbow 模型记录癌症进展的自然史
  • 批准号:
    10437462
  • 财政年份:
    2022
  • 资助金额:
    $ 38.77万
  • 项目类别:
Defining the role of type III collagen and the collagen-binding receptor DDR1 in metastatic dormancy
定义 III 型胶原和胶原结合受体 DDR1 在转移休眠中的作用
  • 批准号:
    10439836
  • 财政年份:
    2020
  • 资助金额:
    $ 38.77万
  • 项目类别:
Defining the role of type III collagen and the collagen-binding receptor DDR1 in metastatic dormancy
定义 III 型胶原和胶原结合受体 DDR1 在转移休眠中的作用
  • 批准号:
    10653992
  • 财政年份:
    2020
  • 资助金额:
    $ 38.77万
  • 项目类别:
Protrusion plasticity during in vivo tumor cell migration
体内肿瘤细胞迁移过程中的突出可塑性
  • 批准号:
    9321473
  • 财政年份:
    2016
  • 资助金额:
    $ 38.77万
  • 项目类别:
Protrusion plasticity during in vivo tumor cell migration
体内肿瘤细胞迁移过程中的突出可塑性
  • 批准号:
    9534544
  • 财政年份:
    2016
  • 资助金额:
    $ 38.77万
  • 项目类别:
Core B - Advance Imaging Core
核心 B - 高级成像核心
  • 批准号:
    10602538
  • 财政年份:
    2009
  • 资助金额:
    $ 38.77万
  • 项目类别:
Core B - Advance Imaging Core
核心 B - 高级成像核心
  • 批准号:
    10397005
  • 财政年份:
    2009
  • 资助金额:
    $ 38.77万
  • 项目类别:

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机构外的生活:1900 - 1960 年心理健康善后护理的历史
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