Confinement, Jamming, and Adhesion in Cancer Cells Dissociating from a Collectively Invading Strand.

Abstract

When cells in a primary tumor work together to invade into nearby tissue, this can lead to cell dissociations-cancer cells breaking off from the invading front-leading to metastasis. What controls the dissociation of cells and whether they break off singly or in small groups? Can this be determined by cell-cell adhesion or chemotactic cues given to cells? We develop a physical model for this question, based on experiments that mimic aspects of cancer cell invasion using microfluidic devices with microchannels of different widths. Experimentally, most dissociation events ("ruptures") involve single cells breaking off, but we observe some ruptures of large groups (~20 cells) in wider channels. The rupture probability is nearly independent of channel width. We recapitulate the experimental results with a phase-field cell motility model by introducing three different cell states (follower, guided, and high-motility "leader" cells) based on their spatial position. These leader cells may explain why single-cell rupture is the universal most probable outcome. Our simulation results show that cell-channel adhesion is necessary for cells in narrow channels to invade, and strong cell-cell adhesion leads to fewer but larger ruptures. Chemotaxis also influences the rupture behavior: Strong chemotaxis strength leads to larger and faster ruptures. Finally, we study the relationship between biological jamming transitions and cell dissociations. Our results suggest unjamming is necessary but not sufficient to create ruptures.