Cluster size distribution of cells disseminating from a primary tumor

The first stage of the metastatic cascade often involves motile cells emerging from a primary tumor either as single cells or as clusters. These cells enter the circulation, transit to other parts of the body and finally are responsible for growth of secondary tumors in distant organs. The mode of dissemination is believed to depend on the EMT nature (epithelial, hybrid or mesenchymal) of the cells. Here, we calculate the cluster size distribution of these migrating cells, using a mechanistic computational model, in presence of different degree of EMT-ness of the cells; EMT is treated as given rise to changes in their active motile forces (μ) and cell-medium surface tension (Γ). We find that, for (μ > μmin, Γ > 1), when the cells are hybrid in nature, the mean cluster size, N ¯ ∼ Γ 2 . 0 / μ 2 . 8, where μmin increases with increase in Γ. For Γ ≤ 0, N ¯ = 1, the cells behave as completely mesenchymal. In presence of spectrum of hybrid states with different degree of EMT-ness (motility) in primary tumor, the cells which are relatively more mesenchymal (higher μ) in nature, form larger clusters, whereas the smaller clusters are relatively more epithelial (lower μ). Moreover, the heterogeneity in μ is comparatively higher for smaller clusters with respect to that for larger clusters. We also observe that more extended cell shapes promote the formation of smaller clusters. Overall, this study establishes a framework which connects the nature and size of migrating clusters disseminating from a primary tumor with the phenotypic composition of the tumor, and can lead to the better understanding of metastasis.Author summary: In the process of metastasis, tumor cells disseminate from the primary tumor either as single cells or multicellular clusters. These clusters are potential contributor to the initiation of secondary tumor in distant organs. Our computational model captures the size distribution of migrating clusters depending on the adhesion and motility of the cells (which determine the degree of their EMT nature). Furthermore, we investigate the effect of heterogeneity of cell types in the primary tumor on the resultant heterogeneity of cell types in clusters of different sizes. We believe that the understanding the formation and nature of these clusters, dangerous actors in the deadly aspect of cancer progression, will be useful for improving prognostic methods and eventually better treatments.