A biophysical model of Epithelial-Mesenchymal Transition uncovers the frequency and size distribution of Circulating Tumor Cell clusters across cancer types
Authors: Bocci Federico , Jolly Mohit Kumar , Onuchic José Nelson 
Published: February 2019

The gain of cellular motility via the epithelial-mesenchymal transition (EMT) is considered crucial in the metastatic cascade. Cells undergoing EMT to varying extents are launched into the bloodstream as single circulating tumor cells (CTCs) or multi-cellular clusters. The frequency and size distributions of these multi-cellular clusters has been recently measured, but the underlying mechanisms enabling these different modes of migration remain poorly understood. We present a biophysical model that couples the epithelial-mesenchymal phenotypic transition and cell migration to explain these different modes of cancer cell migration. With this reduced physical model, we identify a transition from individual migration to clustered cell migration that is regulated by the rate of EMT and the degree of cooperativity between cells during migration. This single cell to clustered migration transition can robustly recapitulate cluster size distributions observed experimentally across several cancer types, thus suggesting the existence of common features in the mechanisms of cell migration during metastasis. Furthermore, we identify three main mechanisms that can facilitate the formation and dissemination of large clusters: first, mechanisms that prevent a complete EMT and instead increase the population of hybrid Epithelial/Mesenchymal (E/M) cells; second, multiple intermediate E/M states that give rise to heterogeneous clusters formed by cells with different epithelial-mesenchymal traits; and third, non-cell-autonomous induction of EMT via cell-to-cell signaling that gives rise to spatial correlations among cells in a tissue. Overall, this biophysical model represents a first step toward bridging the gap between the molecular and biophysical understanding of EMT and various modes of cancer cell migration, and highlights that a complete EMT might not be required for metastasis.

Popular summary

The Epithelial-Mesenchymal Transition (EMT) has been identified as the first step that enables cancer metastases; through this process, cancer cells gain the motility necessary to migrate and invade. Cancer cells that undergo EMT can enter the circulatory system both as single cells or as multi-cellular clusters. While single cells are generally more frequent in human cancers, clusters are more prevalent in aggressive cancers that metastasize more. Although the molecular mechanisms of EMT are relatively conserved across cancers, how different cancers exhibit such tremendous variability in terms of cell migration remains unclear. We develop a biophysical model to investigate how EMT regulation at a single cell level can give rise to single cell and clustered cell migration. This model quantitatively reproduces size distributions of circulating tumor cell clusters reported in human circulation and mouse models, therefore identifying a unifying set of principles governing cell migration across different cancer types. Moreover, a model where cells only undergo a partial EMT to a hybrid epithelial/mesenchymal state can recapitulate different features observed in collective cancer cell migration, including the frequency of large clusters and flat distributions that cannot be captured by a model of complete EMT. Besides partial EMT, we propose additional mechanisms that can facilitate the formation of large tumor cell clusters, including multiple hybrid epithelial/mesenchymal cell states and signaling between cells that enables noncell autonomous EMT induction. Therefore, our general picture suggests universal traits in the migration of cancer cells and challenges the necessity of a complete EMT for cancer metastasis.