The effects of cellular interactions on the sizes, composition, and dynamics of migrating cancer cell clusters

Collective migration plays an important role in metastasis, promoting survival of migrating clusters and increasing malignancy. Hybrid cells in intermediate EMT states have been attributed to be responsible for collective migration. These are cells with both epithelial and mesenchymal characteristics allowing them to migrate while maintaining interactions with other cells. While the benefits of collective migration are known, it is unclear what determines the sizes and compositions of the resulting clusters. Here, we present a cellular Potts model that models cellular adhesions and chemotactic responses of cancer cells to understand how these physical properties affect the sizes and composition of migrating clusters. From our simulations, we find that high chemotactic response drives individualistic behavior and promotes smaller clusters, whereas high cellular adhesion drives collective behavior and results in larger clusters. Epithelial cells are found to metastasize in heterogenous clusters consisting of both hybrid and epithelial cells. In heterogenous clusters, hybrid cells serve as leader cells and epithelial cells act as followers. However, heterogenous clusters are less stable than homogenous ones consisting of only hybrid cells as they often undergo further dissociation. Although hybrid cells bring epithelial cells along in a migrating cluster, increasing the fraction of hybrid cells leads to an overall decrease in the number of migrating epithelial cells. This highlights the interplay between competition and collaboration of the two cell types. Lastly, the motility and detachment timings of the clusters are characterized. Detachment timings are highly stochastic whereas motility correlates positively with the number of hybrid cells and negatively with the number of epithelial cells in a cluster. Overall, our model provides a framework to study the effects of cellular interactions on collective migration.