Physical mechanisms driving mesendoderm collective cell migration

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One of the main features of life is movement, either as a single entity or in groups. Collective cell migration is characterizedas the behaviour of a group of cells which moves together more efficiently than its components in isolation. It is a fundamental process seen in all multicellular animals and is essential for physiological functions such as wound healing and immune cell surveillance in adults. During embryonic development, collective cell migration is a hallmark of cellular rearrangements and ensures accurate formation of organs and tissues. Invading and metastatic cancer cells can also migrate as collectives thus making this process highly relevant during cancer metastasis.The mechanisms guiding collectively migrating cells vary and can depend on inherent cellular reorganisation events such as establishment of leader and follower (trailing) cells and on external signals from the microenvironment which act as guidance cues ("inputs"), ultimately generating a collective response for directional migration. The cells in the collective respond to and communicate with each other through biochemical and physical interactions enabled by cell-cell connections (adhesions), thereby coordinating efficient movement. Guidance as well as the intercellular communication can be mediated through physical/mechanical, chemical and/or electrical cues. Extensive studies have revealed the role of major signalling molecules (chemokines) in collective migration. However, recent findings emphasise that mechanical stimuli (pulling, pushing, shear) and physical properties of the surrounding may be equally important for cell migration. Yet, our knowledge of how these physical factors contribute to collective cell migration within living organisms and the underlying mechanisms remain very limited.The zebrafish embryo constitutes an ideal model organism to study cell migration, as the embryos are transparent and perfectly suited for live cell imaging. Furthermore, it is a highly accessible system where specific cells can be transferred between different embryos (transplantations) or isolated from the embryo for ex vivo experiments. We will focus our research on the mesendoderm tissue, which is a cell collective that is highly conserved in vertebrates and is fundamental for early embryonic development. Mesendoderm cells migrate as a collective along the future head-tail body axis of the embryo and failure in precise collective migration results in embryonic defects in eye and brain and body axis malformations leading to organ degeneration or early embryonic death.To address the physical basis of mesendoderm collective migration, we will use a highly interdisciplinary approach combining methods and tools from biology, physics and theoretical modelling. We will identify mechanical cues and physical properties of the microenvironment that influence collective migration, and investigate how these signals are transduced through the collective. We will further study how physical barriers and adhesive surfaces contribute to cell migration. Finally, a mathematical model will be developed that aims to recapitulate polarization and directional movements of a collective based on the minimal essential physical parameters.In summary, the outcomes of the proposed research will have significant impact on our understanding of physical mechanisms that drive collective cell migration of mesendoderm cells in the embryo. This will be essential in expanding our knowledge of embryonic development and will also serve as a framework to understand behaviours of other collectively moving systems in physiological and pathological contexts.