Mechanical adaptation of lamellipodial actin

The ability of cells to migrate is a ubiquitous feature of the eukaryotic world. Development, regeneration and immune surveillance of animals critically depend on it and a plethora of pathologies result from aberrant single cell motility, the most prominent being metastatic spread of tumors. When a migrating cell encounters an obstacle it might either go around it or push it away. All pushing forces are generated by polymerizing filaments of the actin cytoskeleton. We found that in a pushing cell, the leading edge adapts the force it generates to the counter-force it experiences and that it does so by regulating the number of pushing filaments. Our data together with theoretical modeling suggests that this adaptation is an emergent property of the special geometrical organization of the protruding actin cytoskeleton. In the proposed study, we want to use a combination of biophysical methods, quantitative fluorescence imaging and correlative light microscopy and three dimensional electron microscopy to investigate how exactly the geometry of the actin network changes when a cell experiences a counter force and when a cell makes a directional turn. By directly focusing on the force-generating machinery, we will be able to develop a comprehensive quantitative model of i) how cells respond to mechanical forces and ii) how cells implement directional or shape changes. Our investigations are highly relevant beyond the fundamental biophysical understanding of cell migration and will also shed light on fundamental processes like endocytosis, vesicle trafficking, cytokinesis and intracellular pathogen movement, which are all driven by the same type of actin dynamics.

Cells continuously migrate through the organism and this function is decisive for development, regeneration and immune responses. Goal of the project was to better understand how a migrating single cell responds to obstacles that are in its way. Does the cell circumvent or push away the obstacle? How does the cytoskeleton, the force generating and transducing unit of the cell execute these decisions? In the course of the project we generated decisive knowledge on these issues. E.g. we found that immune cells efficiently identify the "path of least resistance" and that they employ not only their cytoskeleton but also their nucleus to select the path. Furthermore we uncovered a mechanism how the actin cytoskeleton of a migrating cell generates the force to enlarge a small pore in the environment in order for the cell body to pass through.