Abstract Summary/Description
Metastasis, the spread of cancer from a primary tumor to distant sites, is driven by coordinated cell behaviors within the tumor microenvironment. A key mechanism underlying metastasis is collective cancer cell migration, which significantly impacts cancer progression and patient outcomes. Experimental studies using spatiotemporal genomic and cellular analysis have uncovered the phenotypic heterogeneity within invading cancer cell populations, distinguishing leader cells—phenotypically stable and highly invasive—from follower cells, which exhibit phenotypic plasticity and limited invasiveness. Despite these advancements, the biophysical properties and interactions governing collective invasion remain poorly understood. To address this knowledge gap, we developed a cell-based computational model based on the cellular Potts model framework to investigate the interplay between leader cell migration, follower cell proliferation, and leader-follower interactions during collective invasion. The model distinguishes between single cell invasion and collective invasion by quantifying invasive area vs. infiltrative invasion area, single vs. clustered cell breakoff, invasive stalk number and height. Our simulations reveal that leader cell migration, leader-follower adhesion, and follower proliferation are critical determinants of collective cancer migration. These findings provide novel insights into the biophysical mechanisms driving collective invasion.
