Integrating mechanical and biochemical signals in cell migration through membrane dynamics

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Cells respond to a myriad of cues from their environment, including mechanical signals from the extracellular matrix and biochemical cues from growth factors and cytokines. How these different types of signal are integrated to produce the appropriate cellular response is not known. We aim to determine how migrating cells decode their environment to move efficiently in complex environments, and understand how cells are able to integrate different types of signal to generate a coordinated response. Migrating cells respond to chemical (chemotaxis), extracellular matrix ligand (haptotaxis) and physical (durotaxis) stimuli by recognising signals at the cell surface. The plasma membrane serves as the physical boundary of the cells, and many signalling processes are organised at this junction between the intra- and extra-cellular environments. Cells sense growth factors/cytokines through signalling receptors, and extracellular matrix properties through cell-matrix adhesion complexes, and hence the availability of such receptors at the membrane (regulated by vesicle trafficking) is of major importance. In addition, the plasma membrane has been shown to control cell behaviour by exerting force (tension) on the underlying cytoskeleton. We hypothesise that membrane dynamics, including vesicle trafficking and membrane tension, orchestrate signals at the plasma membrane to integrate different classes of stimuli and direct cell migration and invasion. We will use direct measurements of localised signalling, forces exerted at the cell-matrix interface and on the plasma membrane (live cell imaging, super-resolution, FRET/FLIM of biosensors) to determine how cells respond to migratory stimuli. Using proteomics, we will establish how signalling networks are reorganised to allow migrating cells to adapt to changes in the physical and biochemical environment. This information will be used to inform mathematical models, to understand how these seemingly independent signalling networks are integrated. By combining state-of-the-art imaging approaches with proteomics and computational models in an iterative process, well will build a comprehensive understanding of how signalling networks are re-wired in the face of the changing landscape faced by cells migrating within complex microenvironments.