Project 2: Cell Migration in Mechanically Complex Microenvironments

癌症是一种复杂的系统，通常与强大的纤维炎症间质反应有关，或者 促结缔组织反应。这一点非常相关，因为现在已经认识到，在许多实体肿瘤中，间质 隔室及其局部微环境对疾病进展有显著影响。穿透疾病 进展这种促结缔组织再生反应持续并经常加剧，为恶性肿瘤提供关键支持 细胞进展为侵袭性疾病，通常是完全转移的疾病，同时也提供了无药物的避难所 这限制了小分子疗法的使用。同样，即使是疾病的最早阶段也与 随着疾病进展而进化的强大的免疫反应。在这里，肿瘤微环境似乎 形成了免疫逃避的避难所，事实上，部分是由渗透的免疫细胞组成的，这些细胞具有 被颠覆成为促进肿瘤进展的积极合作者。有趣的是，虽然健壮 生化刺激存在于肿瘤中，它们不是唯一的因素。这些微环境还提供了 强健的身体信号，共同促进疾病的进展。例如，在实体肿瘤中，有 深刻影响细胞外基质硬度、组成和结构的基础作用 结果。然而，到目前为止，基质硬度和基质硬度的分子和物理机制 影响肿瘤细胞行为的结构和它们的相关贡献还不是很清楚。在这里，我们 提出具体和集成的实验和建模，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。数据的量化分析和参数化将有助于模型的建立 开发和模型预测将在实验中得到验证。具体地说，我们将采用一系列2D 以及具有不同硬度的3D分析和日益复杂的体系结构，以及多尺度网络 建模，以解析接触引导线索和复杂环境中的趋向性效应的相对贡献 微环境。化学梯度的整合将被用来解析出优势、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讯并调节免疫细胞 渗透性和功能性。因此，我们试图确定操纵可操作的物理特征的区域 肿瘤的发生减少了癌细胞的进展，同时阻碍了免疫逃逸和 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.