Matrix-driven changes in metabolism support cytoskeletal activity to promote cell migration.

The microenvironment provides both active and passive mechanical cues that regulate cell morphology, adhesion, migration, and metabolism. Although the cellular response to those mechanical cues often requires energy-intensive actin cytoskeletal remodeling and actomyosin contractility, it remains unclear how cells dynamically adapt their metabolic activity to altered mechanical cues to support migration. Here, we investigated the changes in cellular metabolic activity in response to different two-dimensional and three-dimensional microenvironmental conditions and how these changes relate to cytoskeletal activity and migration. Utilizing collagen micropatterning on polyacrylamide gels, intracellular energy levels and oxidative phosphorylation were found to be correlated with cell elongation and spreading and necessary for membrane ruffling. To determine whether this relationship holds in more physiological three-dimensional matrices, collagen matrices were used to show that intracellular energy state was also correlated with protrusive activity and increased with matrix density. Pharmacological inhibition of oxidative phosphorylation revealed that cancer cells rely on oxidative phosphorylation to meet the elevated energy requirements for protrusive activity and migration in denser matrices. Together, these findings suggest that mechanical regulation of cytoskeletal activity during spreading and migration by the physical microenvironment is driven by an altered metabolic profile.