Mechanobiology of Vimentin Intermediate Filaments in 3D Collective Cell Migration

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PROJECT SUMMARY: Vimentin intermediate filaments augment cytoskeletal deformability and directed migration of individual mesenchymal cells, but their role in multicellular migration, tractions, and coordination is poorly understood. Such collective migration of mechanically connected cells is crucial for embryonic development, wound healing, and tumor invasion. Gain of vimentin is associated with the epithelial- mesenchymal transition (EMT), where tightly-connected epithelial cells downregulate cell-cell adhesions and acquire an individual mesenchymal phenotype. However, cells that migrate collectively in groups can also express vimentin in combination with cell-cell junctions (e.g. cadherins). For instance, “leader cells” at wound fronts can exhibit an elongated morphology with vimentin, while remaining partially connected to migratory followers. Given these questions, there exists a critical need to elucidate the role of vimentin in leader cells and its contributions to collective cell migration. Our overall objective is to elucidate the functional role of vimentin in leader and follower cells for directed cell motility, multicellular tractions, and cell-cell coordination. In particular, we consider several fundamental questions: 1) How does vimentin affect confined migration and cellular deformability? 2) How does vimentin affect collective tractions? 3) How does vimentin affect cell-cell adhesions and coordinated motility? 4) How do vimentin-high and vimentin-low cells interact during collective migration? Our approach will integrate several complementary technologies for precision measurement of collective cell migration and mechanobiology. MPI: Guo is an Early Stage Investigator with extensive expertise in the mechanics of soft and living materials, including vimentin networks and extracellular matrix. MPI: Wong is an Early Stage Investigator with extensive expertise in collective migration and EMT, particularly single cell tracking and analyses. Co-I: Goldman is a leader in the molecular biology of vimentin. This proposal is structured around 3 aims: elucidate how vimentin affects cell shape, migration and deformability of multicellular collectives in confinement (AIM 1), multicellular tractions in 3D matrix (AIM 2), and collective interactions of “mosaic” spheroids with heterogeneous vimentin expression (AIM 3). Overall, this work will reveal new fundamental insights into the role of vimentin in cell shape, motility, and mechanical integrity in collective migration, with potential implications for tissue morphogenesis and tumor dissemination.