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, Ras 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 Ras expression alters the shape, division orientation, and respreading dynamics of cells as they exit mitosis.

The role of RAS oncogenes in controlling epithelial mechanics.

Mutations in RAS are key oncogenic drivers and therapeutic targets. Oncogenic Ras proteins activate a network of downstream signalling pathways, including extracellular signal-regulated kinase (ERK) and phosphatidylinositol 3-kinase (PI3K), promoting cell proliferation and survival. However, there is increasing evidence that RAS oncogenes also alter the mechanical properties of both individual malignant cells and transformed tissues.

Local synthesis of the phosphatidylinositol-3,4-bisphosphate lipid drives focal adhesion turnover.

Focal adhesions are multifunctional organelles that couple cell-matrix adhesion to cytoskeletal force transmission and signaling and to steer cell migration and collective cell behavior. Whereas proteomic changes at focal adhesions are well understood, little is known about signaling lipids in focal adhesion dynamics. Through the characterization of cells from mice with a kinase-inactivating point mutation in the class II PI3K-C2β, we find that generation of the phosphatidylinositol-3,4-bisphosphate (PtdIns(3,4)P) membrane lipid promotes focal adhesion disassembly in response to changing environmental conditions.

Cell biology: How cancer cells coerce normal cells into tumorigenesis.

The role of altered tissue mechanics in early cancer development is not well understood. A new study reveals how oncogene activation generates force within a tissue to impact cell division in surrounding normal cells, which then contribute to tumour formation.

Oncogenic Signaling Alters Cell Shape and Mechanics to Facilitate Cell Division under Confinement.

To divide in a tissue, both normal and cancer cells become spherical and mechanically stiffen as they enter mitosis. We investigated the effect of oncogene activation on this process in normal epithelial cells. We found that short-term induction of oncogenic Ras activates downstream mitogen-activated protein kinase (MEK-ERK) signaling to alter cell mechanics and enhance mitotic rounding, so that Ras-expressing cells are softer in interphase but stiffen more upon entry into mitosis.