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、物理力和结构结构引导。在这项提案中，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？我们的主要假设是，3D肿瘤微环境中细胞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。我们将使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的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，以描述和测量一组物理参数，这些参数定义了肿瘤细胞的侵袭行为；细胞的运动性(扩散率，D)、趋化反应(持久性，P)和推进力(F)。这些测量将在有和没有靶向治疗的情况下，对具有良好特征的细胞系和乳腺癌患者衍生的原发肿瘤细胞进行，作为化学和机械微环境的函数。这些参数将与疾病分期、临床侵袭性分类和复发时间相关，并将反过来反馈到我们的量化模型中，以告知和改进它们。这些参数的测量将导致对转移迁移的物理调控因素的更完整的描述，并识别干扰转移细胞迁移的新的治疗靶点。这项提议将回答以下问题：细胞物理力的产生是否与转移的肿瘤细胞潜力相关？周围免疫细胞和血管细胞创造的化学微环境是否控制转移的迁移表型？实体瘤ECM机械硬度的增加是否通过细胞力的增加而使迁移表型得以实现？微管动力学和选定的微管蛋白翻译后修饰在细胞迁移过程中对不同的ECM化学机械信号做出反应的作用是什么？微管靶向化疗药物如何调节这些行为，ECM化学梯度和机械力与常驻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的3D化学和机械微环境条件的必要性。有了这项建议，我们正在整合来自物理科学学科的新的、定量的方法，以系统和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。我们的工作承诺了解微环境在转移中的作用，并有可能将这种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 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.