Intermittent attachments form three-dimensional cell aggregates with emergent fluid properties

In living systems across developmental and cancer biology, populations of cells on surfaces organize themselves into aggregates that mediate function and disease. Recent experimental studies have identified that such aggregates can behave as fluid-like droplets with emergent properties such as surface tension, yet the physical origin of these properties is not well understood. Here, we develop a minimal cell-based model in which intermittent (i.e. transient) cell-cell and cell-surface attachments mimic the dynamic polarity of motile cells. We find that intermittent attachments are sufficient to generate an effective wetting-dewetting transition, which causes the formation of surface-associated three-dimensional cell aggregates. By comparing simulations with experiments, we predict that cell-surface adhesion explains morphology in aggregates of MDA-MB-231 breast cancer cells, and that chemotherapeutic resistance causes enhanced aggregate shape fluctuations through increased cell attachment strength in populations of OVCAR-3 ovarian cancer cells. Extending the model to account for biased motility, we also predict how heterogeneity in intermittent attachments governs pattern formation during the collective chemotaxis of Dictyostelium discoideum swarms. We show how these experimental observations in multiple biological systems can be explained by quantifiable fluid-like properties of aggregates such as wetting, surface tension, and tissue fluidity, which depend on the strength and intermittency of cell-cell and cell-surface attachments. Together, these results reveal how intermittent attachments generate cell aggregates with emergent material properties, with broad implications for development and cancer.