Polarity signaling within and between cells analyzed in a 1D model of collective cell migration

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Animal tissues are composed of large numbers of cells that together determine tissue shape and function. Collective behavior of cells in tissues is only possible when individual cells coordinate their behavior with their neighbors, by integrating signals that they receive from them or from their environment. During collective cell migration, individual cells employ their autonomous migration machinery for locomotion, while they are coupled to their neighbors through adhesive cell-cell contacts. Collective cell guidance therefore requires that adjacent cells coordinate their motility and polarity systems through intercellular communication. Despite the known importance of collective cell migration during development, tissue repair, and disease, fundamental aspects of how collective cell guidance is achieved remain unclear. A detailed understanding of the mechanisms mediating intercellular communication requires quantitative measurements of relevant structural and signaling parameters both in autonomously and collectively migrating cells. In this discovery research program, we will follow a novel strategy at the interface between biology, engineering, and physics, combining fluorescence-based biosensor measurements in live cells with microfabrication and computational image analyses. Micropatterned substrates with defined geometries will force otherwise heterogeneously behaving cells into predicable migration behaviors. Spatiotemporal patterns of multiple biosensor signals recorded individually can then be aligned to precise behavioral landmarks and their relationship to each other determined. In Aim 1, we will study autonomous signaling in individually migrating cells. We will spatiotemporally map patterns of signaling activities in unpolarized cells, in cells migrating on linear tracks, and during defined migration events, e.g. turning or repolarization. In Aim 2, we will use a simplified model of collective cell migration, where cells migrate collectively as trains on linear or circular micropatterned tracks. We will investigate how interactions between cells inform and modify autonomous signaling activities to achieve collective migration. This research program will establish relationships between critical signaling components and morphological changes, and create a new level of understanding of the complex mechanisms that govern autonomous and collective cell migration. By investigating how the signaling activities required for autonomous and collective cell migration are regulated in time and space, we aim to identify mechanisms of intercellular communication mediating collective cell behavior. Moreover, the proposed research will provide an excellent training opportunity for trainees interested in using cutting-edge technology that links physical approaches to studying fundamental aspects of collective cell behavior.