Plasma Membrane Rigidity Directly Influences Cell Migration

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The fundamental knowledge of cell biomechanics is important to understand the development and advancement of diseases. For instance, it has been recognised that cancer cells differ from healthy ones by a reduced shear stiffness. It has been assumed so far that structural changes of the cytoskeleton and the nucleus solely determine the biomechanical properties of cells. In this context it has not yet been examined which role structural changes of the plasma membrane are playing. In the present project we will analyse, to which extent the lipid composition of the plasma membrane influences the bending stiffness and the migration behaviour of cells. With our worldwide first flicker spectroscopy studies of GPMVs, obtained from clinical samples, we have already shown that there is a correlation between the bending rigidity of isolated plasma membranes and the lipidome of healthy and malignant cells. Within this project the molecular reasons which lead to the alteration of the bending stiffness of the plasma membrane and how far this influences the migration behaviour of cells will be comprehensively examined. The starting point is the investigation of the correlation between the bending stiffness and the molecular composition of "Giant Plasma Membrane Vesicles" (GPMVs). GPMVs are plasma membranes isolated from cells which maintain essentially their complex lipid composition and therefore represent a suitable physiological model. In our project GPMVs are generated from primary cells from tissue samples obtained from breast cancer patients from the Leipzig University hospital. For comparative purposes we will also examine healthy epithelial tissue from the same patient. To complement the investigations with primary cells we will apply a breast cancer cell panel which represents different stages of cancer. The bending stiffness of the GPMVs will be determined by flicker spectroscopy and the (phospho)lipid composition by mass spectrometry and NMR. The correlation between bending stiffness and membrane composition will increase the knowledge which (phospho)lipid classes influence membrane stiffness. In addition we will explore selectively the influence of oxidatively modified membrane lipids on membrane rigidity since the formation of “reactive oxygen species” (ROS) plays also a crucial role in cancer pathogenesis. The correlation of the plasma membrane elasticity and cell migration will be investigated by the migration of single cells through micro channels. By probing the percentage of cells that are able to pass through apertures of various sizes, the squeeze-through time, as well as type of motion after passage will be analyzed in correspondence to membrane rigidity. We expect that a decrease in membrane rigidity facilitates the cell migration through narrow channels.