Project 2: Cell Migration in Mechanically Complex Microenvironments

癌症是复杂的系统，通常与强烈的纤维炎性基质反应相关，或 结缔组织增生反应。这是高度相关的，因为现在认识到，在许多实体瘤中，间质肿瘤是恶性的。 室及其局部微环境显著影响疾病进展。通过疾病 这种促结缔组织增生性反应持续并经常加剧，为恶性肿瘤提供关键支持。 细胞，因为他们的进展，以侵入性和往往完全消化性疾病，同时也提供无毒品庇护所 这限制了小分子疗法的使用。同样，即使是疾病的最早阶段， 一种随着疾病进展而发展的强大免疫反应。肿瘤微环境似乎 形成免疫逃避的庇护所，事实上，部分由浸润的免疫细胞组成， 被颠覆为积极的合作者，使肿瘤进展。有趣的是，虽然强大 虽然生物化学刺激存在于肿瘤中，但它们不是唯一的因素。这些微环境还提供 强烈的身体暗示共同促进疾病进展。例如，在实体瘤中， 细胞外基质的硬度、组成和结构的基本作用， 结果。然而，到目前为止，基质刚度和硬度的分子和物理机制还不清楚。 结构和它们的相对贡献影响肿瘤细胞行为还不是很清楚。这里我们 提出具体和综合的实验和建模，以明确研究物理和分子 肿瘤微环境调节疾病进展的机制， 潜在的癌症遗传学数据的定量分析和参数化将有助于模型的建立 开发和模型预测将进行实验测试。具体来说，我们将采用一系列2D 和3D分析，具有不同的刚度和结构，复杂性不断增加，以及多尺度网络 模型，解析出接触指导线索和durotactic效应在复杂的 微环境化学梯度的整合将用于解析主导、对抗或 化学和物理线索之间的协同作用。此外，我们假设细胞中的物理线索 微环境驱动不同肿瘤细胞群之间的通信并调节免疫细胞 渗透和作用。因此，我们试图确定制度，操纵操作性的物理特性， 减少癌细胞的进展，同时阻碍免疫逃避， 促进抗肿瘤反应。

Cancers are complex systems commonly associated with a robust fibroinflammatory stromal response, or desmoplastic reaction. This is highly relevant as it is now recognized that, in many solid tumors, the stromal compartment and its local microenvironments significantly influence disease progression. Through disease progression this desmoplastic reaction continues and often intensifies, offering critical support to malignant cells as they progress to invasive and often fully metastastic disease while also providing drug-free sanctuaries that limit access of small molecule therapies. Likewise, even the earliest stages of disease are associated with a robust immune reaction that evolves with disease progression. Here tumor microenvironments appear to form sanctuaries for immune evasion and in fact are comprised, in part, of infiltrated immune cells that have been subverted to act as active collaborators that enable tumor progression. Interestingly, while robust biochemical stimuli are present in tumors, they are not the only factor. These microenvironments also provide robust physical cues that conspire to promote disease progression. For instance, in solid tumors there are fundamental roles of extracellular matrix stiffness, composition and architecture that profoundly influence outcome. However, to date, the molecular and physical mechanisms by which matrix stiffness and architecture, and their relative contributions, influence tumor cell behavior are not well known. Here, we propose specific and integrated experiments and modeling to explicitly investigate the physical and molecular mechanisms by which the tumor microenvironment regulates disease progression as a function of the underlying carcinoma genetics. Quantitative analysis and parameterization of data will facilitate model development and model predictions will be tested experimentally. Specifically, we will employ a series of 2D and 3D assays with varying stiffness and architecture of increasing complexity, and multiscale network modeling, to parse out the relative contributions of contact guidance cues and durotactic effects in complex microenvironments. Integration of chemical gradients will be used to parse out dominance, antagonism or synergy between chemical and physical cues. Further, we hypothesize that physical cues in the cellular microenvironment drive communication between different tumor cell populations and regulate immune cell infiltration and function. Thus, we seek to identify regimes where manipulating operant physical characteristics of a tumor reduces carcinoma cell advancement while simultaneously hampering immune evasion and promoting the antitumor response.