Biomechanical Mechanisms of Oncogenic Epithelial to Mesenchymal Transition

癌症是美国的一大死因。虽然细胞分裂失控是肿瘤形成的标志，但癌细胞从原发肿瘤扩散到其他器官，即转移，是导致高死亡率的关键特征。在转移过程中，上皮性癌细胞从原发肿瘤部位分离，并获得高度运动性和/或间充质表型。这些细胞向周围组织和循环/淋巴系统的迁移/入侵导致远端组织的定植和继发性肿瘤的形成。导致肿瘤转移的主要生物学机制是上皮向间充质转化(EMT)。除了在癌症转移中的作用外，EMT还是一个基本的生物学过程，在胚胎发育、伤口愈合和器官纤维化中发挥着重要作用。在EMT过程中，极化的上皮细胞经历了显着的生化和生物结构变化，并获得了具有增强的迁移和侵袭能力的间充质表型。虽然在致癌EMT过程中发生的许多生化信号事件是已知的，但调控致癌EMT的生物力学机制尚未很好地建立。此外，尽管肿瘤微环境可以影响肿瘤的进展，肿瘤硬度的增加是晚期疾病的诊断指标，但关于肿瘤的生物力学性质(即基质硬度)的变化如何影响EMT和转移潜能的信息有限。本研究结合生物物理、分子生物学和定量工程工具来研究致癌EMT的生物力学机制，并探讨组织/基质力学变化如何影响EMT和转移。先进的实验技术将被用来描述不同癌细胞在EMT过程中细胞力学的变化。EMT的几个生物力学指标(即硬度、粘弹性和伸缩性)将与细胞的迁移和侵袭行为相关。除了建立一套独特的EMT生物力学标志物外，这些研究还将提供一种创新的方法，基于细胞的机械表型来定量评估转移潜力。实验技术也将被用来研究底物/基质硬度的变化如何影响致癌EMT的生物力学和生化信号机制。最后，将开发肿瘤细胞脱离和迁移/侵袭的三维多尺度计算模型，这些计算模型将用于开发如何利用细胞力学的变化来减轻转移的新见解。拟议的研究研究将为俄亥俄州立大学的博士后研究科学家和生物医学工程本科生/研究生提供培训，并将被整合到数量生理学的本科课程中。外展活动包括为俄亥俄州超级计算机中心主办的高中生计算建模暑期教育计划做出贡献。

1134201GhadialiCancer is a major cause of death in the United States. Although uncontrolled cell division is a hallmark of tumor formation, the spread of cancer cells from a primary tumor to other organs, i.e. metastasis, is the key feature that leads to high mortality rates. During metastasis, epithelial cancer cells detach from the primary tumor site and acquire a highly motile and/or mesenchymal phenotype. Migration/invasion of these cells into surrounding tissue and the circulatory/lymphatic system leads to colonization of distal tissues and secondary tumor formation. The central biological mechanism responsible for metastasis is known as epithelial to mesenchymal transition (EMT). In addition to its role in cancer metastasis, EMT is a fundamental biological process that plays an important role in embryonic development, wound healing and organ fibrosis. During EMT polarized epithelial cells undergo dramatic biochemical and biostructural changes and acquire a mesenchymal phenotype with enhanced migratory and invasive capacity. Although many of the biochemical signaling events that occur during oncogenic EMT are known, the biomechanical mechanisms governing oncogenic EMT are not well established. Furthermore, although it is well established that the tumor microenvironment can influence cancer progression and that increased tumor stiffness is a diagnostic indicator of advanced disease, there is limited information about how changes in the tumor?s biomechanical properties (i.e. matrix stiffness) influence EMT and metastatic potential.This proposal utilizes a combination of biophysical, molecular biology and quantitative engineering tools to investigate the biomechanical mechanisms governing oncogenic EMT and to investigate how changes tissue/matrix mechanics influences EMT and metastasis. Sophisticated experimental techniques will be used to characterize changes in cellular mechanics during EMT in different cancer cells. Several biomechanical markers of EMT (i.e. stiffness, viscoelasticity and contractility) will be correlated with cell migration and invasion behaviors. In addition to establishing a unique set of biomechanical markers of EMT, these studies will also provide an innovative way to quantitatively assess metastatic potential based on the cell's mechanical phenotype. Experimental techniques will also be used to investigate how changes in substrate/matrix stiffness influence the biomechanical and biochemical signaling mechanisms responsible for oncogenic EMT. Finally, three-dimensional multi-scale computational models of tumor cell detachment and migration/invasion will be developed and these computational models will be used to develop new insights into how changes in cell mechanics may be used to mitigate metastasis. The proposed research studies will provide training for a post-doctoral research scientist and undergraduate/graduate students in biomedical engineering at The Ohio State University and will also be integrated into an undergraduate course in quantitative physiology. Outreach activities included contributing to a summer educational program for high school students in computational modeling hosted by the Ohio Supercomputer Center.