Oncogenic Ras deregulates cell-substrate interactions during mitotic rounding and respreading to alter cell division orientation

Abstract

Oncogenic Ras has been shown to change the way cancer cells divide by increasing the forces generated during mitotic rounding. In this way, RasV12 enables cancer cells to divide across a wider range of mechanical environments than normal cells. Here, we identify a further role for oncogenic Ras-ERK signalling in division by showing that RasV12 expression alters the shape, division orientation and respreading dynamics of cells as they exit mitosis, in a manner that depends on MEK and ERK. Many of these effects appear to result from the impact of RasV12 signalling on actomyosin contractility, since RasV12 induces the severing of retraction fibres that normally guide spindle positioning and provide a memory of the interphase cell shape. In support of this idea, the RasV12 phenotype is reversed by inhibition of actomyosin contractility, and can be mimicked by the loss of cell-substrate adhesion during mitosis. Thus, the induction of oncogenic Ras-ERK signalling leads to rapid changes in division orientation that, along with the effects of RasV12 on cell growth and cell cycle progression, are likely to disrupt epithelial tissue organisation and contribute to cancer dissemination.