Clusters, fingers, and singles: A mechanical landscape of tumor invasion

The useful part

Marcus, Yi Jiang Collective invasion is a key mechanism by which tumors disseminate and metastasize, involving coordinated migration of heterogeneous cell populations. Experimental studies in spheroid-based assays have identified specialized leader and follower cells that work together during this process, but the biophysical rules governing their interaction remain unclear. We present a mechanistic, cell-based computational model using the Cellular Potts framework to investigate how heterotypic adhesion, leader motility, and follower proliferation jointly shape invasion.

How it works

• Leader–follower tumors were simulated across 13 310 parameter sets, and invasion was quantified by invasive and infiltrative areas, finger-like protrusions, solitary defectors, and detached clusters.
• This framework reconciles binary models of invasion with experimental observations of heterogeneity, providing predictive insights into how modulating adhesion and motility may modify invasive behavior.
• From these simulations, we identified four distinct invasion phenotypes: non-invasive, bulk collective, single-cell, and multimodal.
• Multimodal invasion–the coexistence of cohesive strands, solitary cells, and small clusters–emerged as the most prevalent phenotype, particularly under moderate adhesion and high motility.
• Proliferation increased tumor bulk rather than determining invasion mode, which was governed primarily by adhesion and leader motility.

What to take from it

Mapping outcomes across the parameter space revealed sharp transitions between invasion modes, underscoring trade-offs between adhesion and motility in shaping invasion complexity.