Role of vimentin in mammalian cell motility

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ABSTRACT Cell migration is essential to many fundamental processes, including embryonic development, wound repair, and cancer metastasis. Central to this process is the cellular cytoskeleton comprised of three polymeric networks: F-actin, microtubules, and intermediate filaments (IFs). Vimentin is an IF protein that is essential to the mechanical resilience of cells and regulates cross-talk amongst the cytoskeleton, but its role in how cells squeeze through small pores in tissues is poorly understood. We have shown that loss of vimentin enhances cell motility through three-dimensional 3D micro-fluidic channels and protects the nucleus from damage during migration. Vimentin is thought to play a distinct role in the transfer of forces from cell surface matrix adhesions to the nuclear surface, but new evidence suggests that vimentin may also play a more active role in persistent cell motility via its interactions with actin stress fiber formation and microtubule positioning. Still, the specific mechanisms by which vimentin enables 3D migration through dense tissue remains unclear. This project addresses the overarching question: how does vimentin influence cytoskeletal functions, adhesions with the extracellular matrix, and cell-cell interactions to coordinate 3D cell migration? To address this question, we will pursue three sub-projects. First, we will determine the effects of vimentin in cytoskeletal- mediated 3D cell motility. Second, we will identify vimentin’s role in integrin expression and focal adhesion activation, and third, we will identify the mechanisms by which vimentin mediates collective cell migration through extracellular matrix networks. These studies will be conducted in both 2D and 3D settings to define how changes in the cellular environment impact the critical determinants of cytoskeletal polymers in cell motility. We expected that these projects will determine new functional roles of vimentin in cell migration, which has important implications for understanding healthy tissue maintenance and diseases that progress by the migration of cells through tissues.