To lead or to herd: optimal strategies for 3D collective migration of cell clusters.

Cells migrating in clusters play a significant role in a number of biological processes such as embryogenesis, wound healing, and tumor metastasis during cancer progression. A variety of environmental and biochemical factors can influence the collective migration of cells with differing degrees of cell autonomy and inter-cellular coupling strength. For example, weakly coupled cells can move collectively under the influence of contact guidance from neighboring cells or the environment. Alternatively strongly coupled cells might follow one or more leader cells to move as a single cohesive unit. Additionally, chemical and mechanical signaling between these cells may alter the degree of coupling and determine effective cluster sizes. Being able to understand this collective cell migration process is critical in the prediction and manipulation of outcomes of key biological processes. Here we focus on understanding how various environmental and cellular factors influence small clusters of cells migrating collectively within a 3D fibrous matrix. We combine existing knowledge of single-cell migration in 2D and 3D environments, prior experimental observations of cell-cell interactions and collective migration, and a newly developed stochastic model of cell migration in 3D matrices, to simulate the migration of cell clusters in different physiologically relevant environments. Our results show that based on the extracellular environment and the strength of cell-cell mechanical coupling, two distinct optimal approaches to driving collective cell migration emerge. The ability to effectively employ these two distinct migration strategies might be critical for cells to collectively migrate through the heterogeneous tissue environments within the body.