Physical and Chemical Cues in Tumor Cell Migration

细胞迁移本质上是一个物理过程，受细胞外和细胞内化学梯度、物理力和结构结构的指导。在这个提议中，我们正在回答这个问题：肿瘤微环境的物理成分是如何促进转移性迁移的？我们的总体假设是，细胞在三维肿瘤微环境中产生的特定化学梯度和细胞外基质（ECM）的变化能够并增强细胞在转移过程中的迁移。我们将运用物理科学的概念和工具来剖析复杂的化学和物理微环境因素在转移过程中引导细胞迁移。为此，我们建议使用定义良好的模型组织结构，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（扩散性，D），趋化反应（持久性，P）和推进力(F)。这些测量将由具有良好特征的细胞系和乳腺癌患者来源的原发肿瘤细胞进行，作为化学和机械微环境的功能，有或没有靶向治疗。这些参数将与疾病分期、侵袭性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，以告知和完善它们。对这些参数的测量将导致对转移性迁移的物理调节因子的更完整的描述，并确定用于破坏转移性细胞迁移的治疗方法的新靶点。这一建议将回答以下问题：细胞物理力的产生是否与转移性肿瘤细胞的潜能相关？由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机械刚度的增加是否通过细胞力的增加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响应不同的ECM化学力学线索的作用是什么？微管靶向化疗药物如何调节这些行为？个体患者对治疗的敏感性如何受到ECM化学梯度、机械力和驻留肿瘤细胞之间相互作用的影响？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解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。通过这一提议，我们正在整合来自物理科学学科的新颖定量方法，系统而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.