Abstract
Cell migration during the invasion-metastasis cascade requires cancer cells to navigate a spatially complex microenvironment that presents directional choices to migrating cells. Here, we investigate cellular energetics during migration decision-making in confined spaces. Theoretical and experimental data show that energetic costs for migration through confined spaces are mediated by a balance between cell and matrix compliance as well as the degree of spatial confinement to direct decision-making. Energetic costs, driven by the cellular work needed to generate force for matrix displacement, increase with increasing cell stiffness, matrix stiffness, and degree of spatial confinement, limiting migration. By assessing energetic costs between possible migration paths, we can predict the probability of migration choice. Our findings indicate that motility in confined spaces imposes high energetic demands on migrating cells, and cells migrate in the direction of least confinement to minimize energetic costs. Therefore, therapeutically targeting metabolism may limit cancer cell migration and metastasis.
Highlights
We show that when presented with migration choices of varying confinement, MDA-MB-231 cells preferentially migrate in the direction of least confinement to minimize energetic costs
Using a computational model and in vitro experiments, we demonstrate that energetic costs for migration through confined spaces are mediated by a balance between cell and matrix compliance and the degree of spatial confinement to direct migration decision-making
The cellular work required for matrix displacement drives the energy requirements for migration, and these energetic costs exponentially increase with increasing cell stiffness
Summary
We show that when presented with migration choices of varying confinement, MDA-MB-231 cells preferentially migrate in the direction of least confinement to minimize energetic costs. Using a computational model and in vitro experiments, we demonstrate that energetic costs for migration through confined spaces are mediated by a balance between cell and matrix compliance and the degree of spatial confinement to direct migration decision-making. At high degrees of spatial confinement as well as high cell stiffness and/or high matrix stiffness, elevated energetic costs for movement restrict migration into narrower confined spaces. Using this framework, we can accurately predict the probability of migration decisions by calculating the energetic costs between possible migration paths. These findings provide insight into the role of cellular energetics in migration and demonstrate that energetic costs, in part, determine a cell’s ability to navigate complex environments
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