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，物理力和结构体系引导。在这个提案中，我们回答了一个问题：肿瘤微环境的物理成分如何促进转移性迁移？我们的总体假设是，由细胞在3D肿瘤微环境中产生的特定化学梯度和细胞外基质（ECM）的变化能够在转移过程中促进细胞迁移。我们将采用物理科学的概念和工具来剖析在转移过程中引导细胞迁移的复杂化学和物理微环境因素。为此，我们建议使用定义明确的模型组织结构，其中细胞环境受到严格控制，以描述和测量一组定义肿瘤细胞侵袭行为的物理参数;细胞的运动性（扩散率，D），趋化反应（持久性，P）和推进力（F）。这些测量将由充分表征的细胞系和乳腺癌患者来源的原发性肿瘤细胞作为化学和机械微环境的函数进行，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，并将反过来反馈到我们的定量模型中，以提供信息和完善它们。这些参数的测量将导致转移性迁移的物理调节剂的更完整的描述，并确定新的治疗靶点，破坏转移性细胞迁移。这个提议将回答以下问题：细胞物理力的产生是否与转移性肿瘤细胞的潜能相关？周围免疫细胞和血管细胞产生的化学微环境是否控制转移性迁移表型？实体瘤ECM的机械刚度增加是否通过细胞力的增加而使迁移表型成为可能？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对不同ECM化学机械信号的反应是什么？微管靶向化疗药物如何调节这些行为，以及ECM化学梯度和机械力与驻留肿瘤细胞之间的相互作用如何影响个体患者对治疗的敏感性？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细胞迁移的复杂3D化学和机械微环境条件的必要性。通过这项提案，我们正在整合物理科学学科的新的定量方法，以系统地，有力地回答癌症生物学和分子肿瘤学中的基本和复杂问题。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。

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 from 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 chemical 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.