Understanding the control mechanisms of 3D cell migration from new dimensions

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Cell migration in 3D tissue space is of fundamental importance for human biology. However, predicting and programming 3D cell motility remain as major challenges despite of a firm picture of the molecular machineries involved. To fill the knowledge gap between the overwhelming subcellular details such as protein-protein interactions, and the fascinating dynamic patterns exhibited by different cell types in tissue spaces, I will focus on the mesoscale cellular dynamics, namely the migration phenotype transitions of cells in 3D extracellular matrix (ECM). To advance the goal of the parent award, two specific aims will be pursued within the scope of the parent award. These specific aims rely on access to a dedicated fluorescent microscope with advanced photomanipulation modules. In particular, aim 1 will elucidate how migration phenotype is modulated by the spatial-temporal gradient of ECM mechanical cues. I will measure the migration phenotype transition rates which encode the cellular responses to spatial-temporal gradient of ECM mechanics. The ECM mechanical properties will be controlled in real time by taking advantage of photoactivated ECM crosslinks. The result will lead to the construction of quasipotential energy landscape that quantitatively depict the cell migration phenotype plasticity. In aim 2 I will employ photo convertible fluorescent cell markers to determine the migration phenotype signatures of partial Epithelial-Mesenchymal Transition (EMT) states. I will compare the migration phenotype landscape for epithelial, mesenchymal, and partial EMT cells from the same epithelial spheroid treated by TGF-β. I will also corroborate the findings with underlying gene expression networks, therefore integrating upstream and downstream observations to build mechanistic models that explain the initiation and evolution of cell migration mode plasticity. Both aims are inline with the parent award, while improving data quality and further mechanistic insights. To pursue the aims I will purchase a fluorescent microscope equipped with state-of-the-art imaging and photomanipulation modules. This system will replace an aging 8 years old fluorescent microscope, one of the PI’s main instrument. The acquired equipment will be fully allocated to the project supported by the parent award and the research in this application.