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
• 负责人: Jose Javier Bravo-Cordero
• 金额: $ 38万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-15 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10439836
• 关键词: Adult; Aftercare; Binding; Biology; Blood Vessels; Bone Marrow; Brain; Cancer Patient; Cause of Death; Cell Communication; Cell Cycle; Cell Proliferation; Cell physiology; Cells; Cessation of life; Collaborations; Collagen; Collagen Fibril; Collagen Receptors; Collagen Type IV; DDR1 gene; Data; Deposition; Disease; Disseminated Malignant Neoplasm; Down-Regulation; Extracellular Matrix; Fibrillar Collagen; Fibronectins; Gene Expression Profiling; Generations; Genetic Transcription; Goals; Growth; Imaging Device; Immune; Interruption; Intervention; Liver; Lung; Malignant Neoplasms; Measures; Mediating; Messenger RNA; Methodology; Methods; Modeling; Molecular; Neoplasm Metastasis; Non-Fibrillar Collagens; Organ; Outcome; Pathway interactions; Patients; Phenotype; Phosphorylation; Primary Neoplasm; Process; Proteins; Proteome; Proteomics; Reporter; Research Design; Role; STAT1 gene; Seeds; Signal Transduction; Site; Stromal Cells; Tenascin; Testing; Time; Transcript; Tumor-Derived; Work; base; cancer cell; high resolution imaging; imaging approach; improved; in vivo; innovation; migration; multiphoton imaging; neoplastic cell; novel; p38 Mitogen Activated Protein Kinase; prevent; protein expression; receptor binding; second harmonic; stem cells; transcriptomics; tumor; tumor growth

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.

项目摘要/摘要 背景：转移是癌症患者死亡的主要原因。传播肿瘤细胞（DTC） 在治疗后数年或几十年，留下原始肿瘤和种子靶器官来源转移。这 生长的延迟是由称为肿瘤休眠的过程介导的。细胞外基质（ECM） - 肿瘤细胞 相互作用已显示以调节癌症的标志。从原发性肿瘤的生长到迁移， 入侵和转移。但是，ECM敏感性和重塑如何诱导和维持休眠 DTC不清楚。此外，DTC是否会组装育儿支持的ECM壁ni以维持其 表型也是一个未解决的问题。我们将探讨ECM通过休眠进行重塑的假设 细胞通过构建富含胶原蛋白III（COL III）的休眠ECM细分市场来促进肿瘤休眠。 假设：我们的总体假设指出，休眠的癌细胞可以构建自己的“休眠状态 - 通过重塑和沉积维持其表型的Col III丰富的ECM的支持。” 目的：该项目的总体目标是两个方面：1）了解Col III ECM在 休眠支持壁ches的形成和2）确定与胶原蛋白III ECM的相互作用如何 通过DDR1调节休眠 - 反应转变。 具体目的：＃1：确定纤维状胶原蛋白III网络如何贡献建立休眠状态支持 利基。 ＃2：确定胶原受体DDR1调节组装的分子机制 促季度ECM。 研究设计/方法：1）这些方法可用于实时研究休眠细胞的生物学 有限。我们建议使用与休眠模型结合使用的高分辨率成像工具来研究块茎 休眠期间的细胞ECM相互作用。我们一直在开发一种包括：i）的成像方法 多光子成像和第二次谐波生成（SHG）和II）与休眠有关的活动报告家 在休眠期间测量p38/ERK信号传导和细胞周期状态的变化的特定途径。 2）到 分析ECM组成和重塑，我们与Naba博士合作使用定量蛋白质组学。 相关性：该项目在概念和方法论层面上都是创新的。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生态位 维持休眠； 2）Col III/DDR1相互作用在控制休眠中的作用； 3）如何发出IFNG/STAT1信号 通过ECM重塑调节肿瘤休眠； 4）促质量ECM蛋白质组和 LTBP1的增加介导休眠 - 反应转变。我们希望我们的研究有重要的 对生物医学的影响，因为它们会发现调节休眠细胞ECM相互作用的机制， 这将是识别靶标以防止转移的有效方法。