Water and ion flux across cell membranes drives motility of cancer cells within confined spaces.

  • Main finding: Water and ion flux across cell membranes drives motility of cancer cells within confined spaces.

  • Concept: Aquaporin and Na+/H+ pumps concentrate at the leading edge of osmotically locomoting cells.

  • Impact: Motility based on water permeation represents an alternative to actin/myosin–based locomotion.

Metastasizing tumor cells crawl atop other cells and squeeze through narrow channels, or microtracks, in the extracellular matrix (ECM) to reach new tissues. Migration upon two-dimensional surfaces requires actin cytoskeleton polymerization and myosin motor protein contractility, but recent studies have suggested that that confined migration of cancer cells can be actin and myosin independent. Stroka and colleagues hypothesized that cells migrating within a confined environment can generate propulsive force by balancing a net inward flow of ions and water at the cell's leading edge with a net outflow at the trailing edge. The model predicts that ion pumps and water channels in the cell membrane would be spatially biased toward the leading edge, and also that changes to osmolarity in the extracellular environment in front of or behind the cell could affect the velocity or the direction of movement. Consistent with this model, when migration along ECM microtracks was simulated using narrow channels in a microfluidic device, the motility of metastatic breast cancer cells and mouse sarcoma cells toward a chemoattractant occurred even when actin and myosin contractility was inhibited, but this motility was strongly impaired after knockdown of either the water channel aquaporin 5 (AQP5) or the Na+/H+ exchanger NHE1. As the model predicted, both these proteins were distributed in polarized fashion toward the leading edge of migrating cells. Further, hypotonic shock at a cell's leading edge or hypertonic shock at the trailing edge caused changes in cell volume and subsequent reversal in the direction of migration, even when this caused cells to move away from chemotactic signals. These data demonstrate that cell motility within confined environments can be accomplished through an osmotic mechanism despite inhibition of actin polymerization or myosin contractility.

Stroka KM, Jiang H, Chen SH, Tong Z, Wirtz D, Sun SX, et al. Water permeation drives tumor cell migration in confined microenvironments. Cell 2014;157:611–23.

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