Physical and Chemical Cues in Tumor Cell Migration

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 力量和结构建筑。在这项提案中，我们回答了这样一个问题：物理组件如何 肿瘤微环境对转移转移有何影响？我们最重要的假设是 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)在转移过程中启用并增强细胞迁移。我们将把概念和工具应用于 物理科学剖析指导细胞迁移的复杂化学和物理微环境因素 在转移过程中。为了做到这一点，我们建议使用定义明确的组织结构模型，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 细胞的运动性(扩散率，D)、趋化反应(持续性，P)和推进力(F)。这些 将对特征良好的细胞系和乳腺癌患者来源的原发肿瘤细胞进行测量 化学和机械微环境的功能，有和没有靶向治疗。这些参数 将与疾病分期、临床侵袭性分类和复发时间相关，进而将被喂养 回到我们的量化模型，以告知和提炼它们。这些参数的测量将导致更多 转移转移的物理调节因素的完整描述，以及新靶点的确定 干扰转移细胞迁移的治疗技术。该提案将回答以下问题：蜂窝 物理力的产生与转移的肿瘤细胞潜能相关吗？化学微环境是否 由周围的免疫细胞和血管细胞产生的细胞控制转移的迁移表型？这是不是 实体瘤细胞外基质机械硬度的增加通过细胞力的增加使其具有迁移表型？是什么 微管动力学和特定微管蛋白翻译后修饰在细胞迁移过程中的作用 对不同的ECM化学机械信号的反应？微管靶向化疗药物是如何调节的 这些行为以及单个患者对治疗的敏感性如何受到ECM之间的相互作用的影响 梯度、机械力和常驻肿瘤细胞？ 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 系统地去卷积影响肿瘤的复杂三维化学和力学微环境条件 细胞迁移。通过这项提议，我们正在整合来自物理学科的新的、定量的方法 系统和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的科学 肿瘤学。我们的工作承诺了解微环境在转移中的作用，并有可能 将这些知识“转化”为实际的临床成果。

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..