Tumour-cell metastasis is complex, but the most basic feature is cell movement — away from the primary tumour through the extracellular matrix (ECM). Cell motility involves remodelling of the cytoskeleton. As Rho-family GTPases regulate cytoskeletal proteins — through the Rho kinase (ROCK) family — and are often overexpressed in tumours, Sahai and Marshall studied Rho–ROCK signalling in the motility of tumour-cell lines.

The ability of some cell lines (such as A375m2 metastatic melanoma) to invade a three-dimensional ECM-like matrix was almost completely blocked by TAT-C3, which inactivates Rho proteins, or Y27632, which inhibits ROCK proteins; other cell lines (such as BE colon carcinoma) were unaffected. The effects of these inhibitors correlated with the morphology of the invading cells in the matrix. TAT-C3- and Y27632-susceptible cell lines were rounded, with membrane blebs, whereas non-susceptible cells such as BE were elongated, with membrane spikes. To show a causal relationship, the effects of modulating Rho–ROCK signalling on tumour-cell morphology were examined. A375m2 cells treated with TAT-C3 or Y27632 lost their membrane blebs and developed membrane protrusions, whereas activating Rho–ROCK signalling in their less rounded, parental non-metastatic counterparts or in BE cells increased cell rounding. So Rho–ROCK signalling is necessary and sufficient for a round morphology.

Finally, Sahai and Marshall looked at the mechanism of cell motility. Whereas cells that move in an elongated manner localized phosphatidylinositol-3,4,5-trisphosphate to the leading edge and had a polarized Golgi apparatus, rounded A375m2 cells had localized membrane patches of ezrin, orientated in the direction of cell movement. Interfering with ezrin function only inhibited the invasive ability of cells that use rounded movement. Ezrin links the ECM and the cytoskeleton, so movement occurs in response to polarized cell adhesions that 'drag' the cell in one direction.

Interestingly, A375m2 cell movement didn't depend on proteolytic degradation of the matrix. Furthermore, when extracellular proteolysis was blocked, cells that would normally move in an elongated manner (such as BE cells) — with no requirement for Rho–ROCK signalling — started moving in a rounded, Rho–ROCK-dependent way. For some tumour cells, therefore, invasion is only blocked when both proteolysis and Rho–ROCK signalling are inhibited.