Cells receive mechanical cues from the surrounding extracellular matrix (ECM). This has a strong impact on physiology and pathology in a wide range of biological settings. Integrin receptors couple... Show moreCells receive mechanical cues from the surrounding extracellular matrix (ECM). This has a strong impact on physiology and pathology in a wide range of biological settings. Integrin receptors couple the ECM to the intracellular cytoskeleton across the cell membrane through a dynamic multiprotein adhesion complex and mediate bidirectional force transmission. In this research the mechanism of cellular mechanotransduction and its role in aspects of cancer progression are studied, focusing on integrins and other integrin associated proteins. We find that the integrin expression profile of cells regulates the orientation and dynamics of force transmission at cell-matrix adhesions. Additionally, using a novel method to quantify the abundance of a molecule in a cellular complex, we show that substrate rigidity modulates the association between traction forces and molecular composition of cell-matrix adhesions. Using cell microprinting in 3D ECM scaffolds, we determine the relation between tumor-induced remote ECM network orientation and angiogenesis. Lastly, genes that regulate cancer cell migration, force application, and adhesion dynamics are identified. Overall, the work described in this thesis unravels the role of cellular mechanotransduction in different aspects of cancer progression and reveals how the molecular composition of cell-matrix adhesions relates to traction force generation. Show less
Life’s building block is a cell. Different cell types are differentiated by specific functional properties. A white blood cell, for instance, can get rid of bacteria and many muscle cells contract... Show moreLife’s building block is a cell. Different cell types are differentiated by specific functional properties. A white blood cell, for instance, can get rid of bacteria and many muscle cells contract together for proper muscle function. Deformation and force exertion play important roles in these processes. Bacteria have to be physically engulfed by the white blood cell, and the muscle cell has to contract in the right way. In this research we measured how much force cells exert and simultaneously visualized specific proteins. A newly developed technique enabled the visualization of the nanometer-structure of cellular adhesions. We also examined the relationship between cellular shape and orientation of an intracellular network of protein (actin). We discovered that the signal of yet another protein (p130Cas) alters the mechanical behavior of the cell when the stiffness outside the cell changes. Finally, we also examined the structure of other proteins (tubulin and H2B) during cell division. In all these processes we measured how much force a cell exerts on its environment. The results provide important insights in the mechanical component of cellular function and their role in life Show less
