Abstract

During division, cells undergo a series of shape changes, driven by dynamic reorganisation of the actin cytoskeleton and cell adhesions. This begins at mitotic entry when cells round-up to become spherical. At the same time, cells also change their mechanical properties, increasing cortical rigidity. This enables them to push against their external environment and generate the space required for spindle assembly and successful chromosome segregation. I will present our work investigating the regulation of cell shape, mechanics and adhesion during mitosis in both normal epithelial cells and following the activation of Ras oncogenes. We find that short-term Ras induction activates downstream MEK /ERK signalling to enhance cell rounding and stiffening at mitosis. In single cells, these Ras-dependent changes allow cells to round up and divide faithfully when confined underneath stiff hydrogels, a condition which introduces catastrophic errors in chromosome segregation in non-transformed cells. When Ras is activated in cells within an epithelial monolayer, the alterations to mitotic cell mechanics combined with changes in cell/cell adhesion result in mis-orientated, out-of-plane cell divisions and loss of monolayer integrity. These results reveal how oncogenic Ras disrupts the normal cell division process to promote both the initial breakdown of epithelial structure and the subsequent proliferation of individual cells in mechanically stiff tumour-like environments.