An agent-based model of collective cell migration to explore the interplay between leader cells and environmental constraints

Collective cell migration is a central process in development, tissue repair, and cancer invasion, yet how internal coordination among cells interacts with environmental physical constraints in shaping collective migration remains incompletely understood. Here, we present a multilevel agent-based framework that integrates mechanical interactions between migrating cells and their surroundings while allowing the systematic inclusion of behavioral heterogeneity through leader–follower organization. By progressively introducing environmental and cellular complexity, from fixed to mobile obstacles, and from homogeneous groups to leader-directed collectives, we identify general principles governing migration efficiency. Our simulations highlight that effective collective migration emerges from a dynamic interplay between cellular organization and environmental mechanics. In permissive or yielding environments, leader–follower hierarchies, particularly front-positioned and sufficiently numerous leaders, enhance directionality and coherence of the group. In contrast, environmental constraints alone, or poorly organized collectives, limit migration performance. This demonstrates that robust navigation arises not from internal coordination or environmental permissiveness in isolation, but from their reciprocal alignment through continuous mechanical feedback. Together, these results provide a unified mechanistic framework for understanding how cell clusters coordinate behavior to achieve efficient migration in complex and evolving environments.