Molecular Mechanisms of Confined Cell Migration

项目总结/摘要 细胞迁移是胚胎发育、免疫监视、伤口愈合和癌症的组成部分 转移为了穿越组织中的各种生理化学环境，细胞已经被证明是 在不同的迁移模式之间切换。例如，当受到高机械限制时，细胞 已经显示出经历了表型转变为所谓的快速变形虫（前导水泡， 迁移）。快速变形虫样迁移的特征是形成一个领导水泡，这是一个大的 稳定的水泡。在非特异性摩擦的情况下，引导泡中的快速皮质肌动蛋白流动提供了动力 快速的变形虫迁移。以前，我们证明了肌动蛋白帽和捆绑蛋白，Eps 8， 在一系列癌细胞类型内形成前导水泡所需的。然而，在高 在机械限制的情况下，免疫细胞也显示出采用快速的变形虫迁移。因此，我们认为， 癌细胞和免疫细胞可以利用类似的在封闭环境中迁移的方法。虽然似乎 癌细胞和免疫细胞可能共享转换为快速变形虫迁移的类似机制（即， 限制传感），癌症和免疫细胞是否需要相同的一套因子来经历快速的免疫反应。 变形虫迁移是未知的。因此，使用体外和体内方法，拟议的工作将 确定癌症和免疫细胞在封闭环境中迁移所需的分子机制， 环境.这是重要的，因为阐明这些机制是合理性的第一步 发展所谓的“migratastics”，防止或减少不健康的（癌），但不迁移 健康（免疫）细胞。

PROJECT SUMMARY/ABSTRACT Cell migration is integral to embryonic development, immune surveillance, wound healing, and cancer metastasis. In order to traverse the varied physiochemical environments in tissues, cells have been shown to switch between distinct migration modes. For instance, when subjected to high mechanical confinement, cells have been shown to undergo a phenotypic transition to what has been termed, fast amoeboid (leader bleb- based) migration. Fast amoeboid migration is characterized by the formation of a leader bleb, which is a large and stable bleb. With non-specific friction, a rapid cortical actin flow in leader blebs provides the motive force for fast amoeboid migration. Previously, we demonstrated that the actin capping and bundling protein, Eps8, is required for leader bleb formation within a range of cancer cell types. However, under conditions of high mechanical confinement, immune cells have also been shown to adopt fast amoeboid migration. Therefore, cancer and immune cells can utilize similar methods of migration in confined environments. Although it appears that cancer and immune cells may share similar mechanisms for switching to fast amoeboid migration (i.e., confinement sensing), whether cancer and immune cells require the same suite of factor(s) to undergo fast amoeboid migration is not known. Accordingly, using in vitro and in vivo approaches, the proposed work will determine the molecular mechanism(s) required by cancer and immune cells for migration in confined environments. This is significant as elucidating these mechanisms is a required first step for the rationale development of so-called “migrastatics,” which prevent or abate the migration of unhealthy (cancerous) but not healthy (immune) cells.