Cluster size dependent transition from chemorepulsion to chemoattraction in malignant lymphocytes

Collective chemotaxis plays a crucial role in coordinating multicellular motion in immune response, tissue development, and cancer invasion. Our in vitro experiments show that lymphocyte clusters, in the presence of a high chemokine (CCL19) gradient, transition from chemo-repulsion for single-cells and small clusters to chemo-attraction for large multicellular clusters. The physical mechanism driving this transition remains unknown. We model the dynamics of these clusters using an agent-based framework that includes cell adhesion, gradient sensing, and stochastic switching in chemotactic response. Our model hypothesizes that beyond a critical local concentration threshold, individual cells stochastically transition to a chemo-repulsive state. Simulations based on this mechanism quantitatively reproduces the experimentally observed transition from chemo-repulsion to chemo-attraction with an increase in cluster size. The crossover emerges from cluster fluidity and the curvature of the cluster boundary, which together modulate the net chemotactic response. These findings provide a mechanistic framework linking single-cell response to emergent patterns of collective migration and highlight how cluster geometry and internal rearrangements modulate chemotactic efficiency.