Molecular Mechanisms of Confined Cell Migration

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.