Physical and Chemical Cues in Tumor Cell Migration

肿瘤细胞迁移中的物理和化学线索

• 批准号: 8309478
• 负责人: Cynthia A. Reinhart-King
• 金额: $ 41.42万
• 依托单位: CORNELL UNIVERSITY
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8309478
• 关键词: Acetylation; Address; Adhesions; Affect; Architecture; Autocrine Communication; Back; Behavior; Biological Models; Biology; Blood Vessels; Cancer Biology; Cancer Patient; Cell Line; Cell Polarity; Cells; Centrosome; Chemicals; Chemotaxis; Classification; Clinical; Collagen; Complex; Cues; Cytoskeleton; Discipline; Disease; Disseminated Malignant Neoplasm; Distant; Drug Delivery Systems; Engineering; Environment; Epithelial; Extracellular Matrix; Gel; Generations; Goals; Immigration; Immune; Individual; Knowledge; Lead; Malignant - descriptor; Malignant Neoplasms; Measurement; Measures; Mechanics; Membrane Protein Traffic; Metastatic to; Methodology; Microfabrication; Microtubules; Modeling; Molecular; Morbidity - disease rate; Movement; Neoplasm Metastasis; Nodule; Normal Cell; Palpable; Paracrine Communication; Patients; Pharmaceutical Preparations; Phenotype; Physics; Polymers; Post-Translational Protein Processing; Primary Neoplasm; Process; Property; Recurrence; Relative (related person); Role; Scientist; Signal Transduction; Signaling Molecule; Site; Solid Neoplasm; Speed; Staging; Stromal Cells; Structure; Taxane Compound; Time; Tissue Model; Tissues; Translating; Tubulin; Work; cancer cell; cell growth; cell motility; chemical function; chemotherapy; crosslink; density; extracellular; feeding; in vitro Model; in vivo; malignant breast neoplasm; migration; molecular oncology; mortality; nano; neoplastic cell; neuronal cell body; new therapeutic target; novel; physical process; physical property; physical science; response; scaffold; taxane; therapeutic target; tool; tumor

Cell migration is inherently a physical process, guided by extracellular and intracellular chemical gradients, physical forces and structural architectures. In this proposal, we are answering the question: How do the physical components of the tumor microenvironment contribute to metastatic migration? Our overarching hypothesis is that specific chemical gradients created by cells within the 3D tumor microenvironment and changes in extracellular matrix (ECM) enable and enhance cell migration during metastasis. We will employ concepts and tools t>om in the physical sciences to dissect the complex chemical and physical microenvironmental factors guiding cell migration during metastasis. To do this, we propose to use well-defined model tissue constructs where the cellular environment is tightly controlled to describe and measure a set of physical parameters that define the invasive behavior of tumor cells; the motility of a cell (Diffusivity, D), chemotactic response (Persistence, P), and the propulsive force (F). These measurements will be made of well-characterized cell lines and breast cancer patient-derived primary tumor cells as a function of the chemical and mechanical microenvironments, with and without targeted therapeutics. These parameters will be correlated with disease stage, clinical classification of invasiveness and time to recurrence and will in turn be fed back to our quantitative models to inform and refine them. Measurement of these parameters will lead to a more complete description of the physical regulators of metastatic migration, and the identification of novel targets for therapeutics which disrupt metastatic cell migration. This proposal will answer the following questions: Does cellular physical force generation correlate with the metastatic tumor cell potential? Does the chemical microenvironment created by surrounding immune cells and vascular cells control the metastatic migratory phenotype? Does the increased mechanical stiffness of solid tumor ECM enable the migratory phenotype via increases in cell force? What is the role of microtubule dynamics and selected tubulin posttranslational modifications in the process of cell migration in response to distinct ECM chemomechanical cues? How do microtubule-targeting chemotherapeutic drugs modulate these behaviors and how is individual patient sensitivity to therapy affected by the interplay between ECM cheniical gradients and mechanical forces and resident tumor cells? This work represents a paradigm shift over traditional 2D cell migration studies as it underscores the need to systematically de-convolve the complex 3D chemical and mechanical microenvironmental conditions affecting tumor cell migration. With this proposal we are integrating novel, quantitative methodologies from the discipline of physical sciences to systematically and robustly answer fundamental and complex questions in cancer biology and molecular oncology. Our work promises to understand the role of microenvironment in metastasis and has the potential of "translating" this knowledge into actual clinical gains..

细胞迁移本质上是一个物理过程，由细胞外和细胞内的化学梯度、物理性质和生物学性质引导。 力和结构体系。在这个提案中，我们回答了这样一个问题： 肿瘤微环境的改变会导致转移性转移吗我们的首要假设是 三维肿瘤微环境中细胞产生的化学梯度和细胞外基质的变化 (ECM)在转移过程中使能并增强细胞迁移。我们将使用概念和工具， 物理科学，以剖析复杂的化学和物理微环境因素引导细胞迁移 在转移过程中。为了做到这一点，我们建议使用定义明确的模型组织结构，其中细胞环境 被严格控制以描述和测量一组定义肿瘤侵袭行为的物理参数 细胞;细胞的运动性（扩散性，D），趋化反应（持久性，P）和推进力（F）。这些 将对充分表征的细胞系和乳腺癌患者来源的原发性肿瘤细胞进行测量， 化学和机械微环境的功能，有和没有靶向治疗。这些参数 将与疾病阶段、侵袭性的临床分类和复发时间相关， 回到我们的定量模型中，为它们提供信息并加以完善。这些参数的测量将导致更多的 完整描述了转移性迁移的物理调节剂，并确定了新的靶点， 破坏转移性细胞迁移的治疗方法。该提案将回答以下问题： 物理力的产生与转移性肿瘤细胞的潜能相关吗？化学微环境 由周围的免疫细胞和血管细胞创造的控制转移迁移表型的细胞？是否 实体瘤ECM的机械刚度增加通过细胞力的增加使迁移表型成为可能？是什么 微管动力学和选择的微管蛋白翻译后修饰在细胞迁移过程中的作用， 对不同ECM化学机械信号的反应微管靶向化疗药物如何调节 这些行为以及个体患者对治疗的敏感性如何受到ECM化学之间的相互作用的影响， 梯度和机械力与肿瘤细胞的关系 这项工作代表了传统2D细胞迁移研究的范式转变，因为它强调了需要 系统地解卷积影响肿瘤的复杂3D化学和机械微环境条件 细胞迁移有了这个建议，我们正在整合新的，定量的方法，从学科的物理 科学系统地，有力地回答癌症生物学和分子生物学中的基本和复杂问题， 肿瘤学我们的工作有望了解微环境在转移中的作用，并有可能 将这些知识“转化”为实际的临床收益。