Saturday, November 23, 2024
11/23/2024
PROJECT SUMMARY: Vimentin intermediate filaments in the cytoskeleton play an underappreciated physiological role in epithelial tissue development, repair, and tumor progression. In particular, vimentin knockout impairs mouse mammary gland development and regeneration in vivo, and disrupts 2D collective cell migration in vitro. Gain of vimentin is also associated with the epithelial-mesenchymal transition (EMT), where tightly-connected epithelial cells downregulate cell-cell adhesions and increase motility. For instance, “leader cells” at wound fronts can exhibit an elongated morphology with vimentin, while remaining partially connected to migratory followers. Indeed, a combination of vimentin and keratin 14 are associated with partial EMT states in genetically engineered mouse models of cancer. Nevertheless, the functional role of vimentin in multicellular migration, tractions, and coordination remains poorly understood, particularly in 3D matrix. Our long-term goal is to elucidate how the mechanobiology of the cytoskeleton regulates collective migration in organ formation, tissue repair, and disease. This goal requires addressing several fundamental questions: 1) How does vimentin affect directed migration and cellular deformability? 2) How does vimentin affect collective tractions? 3) How does vimentin affect cell-cell adhesions and collective migration? 4) How do vimentin-high and vimentin-low cells interact during collective migration? Based on these challenges, our objective is to elucidate the role of vimentin in collective migration through directed cell motility, multicellular tractions, as well as cell-cell coordination. 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 a New 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.
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