A biophysical model of Epithelial-Mesenchymal Transition uncovers the frequency and size distribution of Circulating Tumor Cell clusters across cancer types

Abstract

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 multicellular 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 epithelialmesenchymal 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-tocell 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. Statement of significanceThe Epithelial-Mesenchymal Transition (EMT) confers motility and invasive traits to cancer cells. These cells can then enter the circulatory system both as single cells or as multi-cellular clusters to initiate metastases.We develop a biophysical model to investigate how EMT at the single cell level can give rise to a solitary or clustered cell migration. This model quantitatively reproduces cluster size distributions reported in human circulation and mouse models, therefore suggesting similar mechanisms in cancer cell migration across different cancer types. Moreover, we show that a partial EMT to a hybrid epithelial/mesenchymal cell state is sufficient to explain both single cell and clustered migration, therefore questioning the necessity of a complete EMT for cancer metastasis.

Quantifying Cancer Epithelial-Mesenchymal Plasticity and its Association with Stemness and Immune Response

“…According to this reduced physical model, a tumor can undergo a transition from primarily single cell-based invasion to collective invasion. Strikingly, this theoretical framework reproduces multiple CTC cluster size distributions measured in patients and mouse models across cancer types, hence suggesting the existence of a unifying set of principles governing cancer cell migration [130].…”

“…To model the migration of CTC clusters, Bocci et al proposed a simple biophysical model where cancer cells can undergo a partial EMT that allows both single-cell and clustered-cell migration, or a complete EMT that only allows single-cell migration [130]. According to this reduced physical model, a tumor can undergo a transition from primarily single cell-based invasion to collective invasion.…”

In vitro cross-talk between metastasis-competent circulating tumor cells and platelets in colon cancer: a malicious association during the harsh journey in the blood

“…They underwent partial EMT and acquired some mesenchymal features, while maintaining epithelial characteristics (i.e., EMT state) ( Williams, Gao, Redfern and Thompson, 2019 ). This hybrid state allows CTC to revert to the epithelial state (i.e., mesenchymal-epithelial transition) ( Bocci, Jolly and Onuchic, 2019 ). Although it has been reported that platelets increase mesenchymal features in cancer cell lines ( Labelle et al, 2011a ), we did not observe this effect in our CTC lines.…”

Dynamics of Phenotypic Heterogeneity Associated with EMT and Stemness during Cancer Progression

“…CTCs can migrate either as individual cells or in units of two or more cell clusters [169]. Various spatiotemporal patterns in EMT phenotypes may influence frequencies and size distributions of CTC clusters [171], which are considered the primary harbingers of metastasis [172]; thus, an understanding of their characteristics, such as size distribution, frequency, ability to traverse capillaries [173], and molecular profiles of their tumor and/or stromal cell populations [174], holds promise in highlighting new therapeutic vulnerabilities. Connecting these traits of CTC clusters to spatiotemporal dynamics of EMT in a primary tumor has yet to be undertaken comprehensively.…”