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

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 signaling in division by showing that RasV12 expression alters the shape, division orientation, and respreading dynamics of cells as they exit mitosis. Many of these effects appear to result from the impact of RasV12 signaling on actomyosin contractility, because RasV12 induces the severing of retraction fibers 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. Finally, we show that RasV12 activation also perturbs division orientation in cells cultured in 2D epithelial monolayers and 3D spheroids. Thus, the induction of oncogenic Ras-ERK signaling 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 organization and contribute to cancer dissemination. [Display omitted] •Oncogenic Ras alters cell shape dynamics during post-mitotic respreading•High contractility in Ras-activated cells breaks mitotic substrate contacts•Loss of substrate cues lead to defects in mitotic spindle orientation•Ras induces out-of-plane divisions in epithelial monolayers and spheroids Cell division is dysregulated in cancer. Ganguli et al. show that activation of an oncogene, Ras, directly alters cell-substrate adhesion and cell shape during progression through mitosis. These changes are accompanied by alterations in mitotic spindle orientation, which lead to out-of-plane divisions and loss of epithelial tissue architecture.