Spatial clustering of adhesion-deficient cells delaysclearance and prolongs geometric unjammingsignatures in epithelial tissues

Abstract

Epithelial tissues maintain mechanical integrity through a balance between cell-cell adhesion and cortical contractility. Disruption of E-cadherin-mediated adhesion is a hallmark of epithelial-mesenchymal transition and cancer progression; yet how local adhesion defects propagate to tissue-scale mechanical changes remains poorly understood. Here, we use a two-dimensional vertex model, varying mutant cell fraction, spatial arrangement, and initial tissue disorder, to investigate how adhesion-deficient cells regulate epithelial mechanics. We show that increasing mutant fraction drives the tissue towards geometric signatures associated with reduced mechanical rigidity, characterised by elevated cellular shape index and increased prevalence of non-hexagonal cells. Crucially, spatial organisation modulates tissue mechanics independently of mutant fraction. For identical mutant fractions, randomly distributed mutants undergo rapid, mutually independent T2-mediated removal, producing only transient shape-index perturbations. Clustered mutants, by contrast, undergo sequential boundary removal, delaying elimination and sustaining elevated shape index in the surrounding tissue; this persistent elevation induces topological disorder that outlasts mutant clearance itself. We show that these signatures arise from the reduced heterotypic interface exposure of interior cluster cells, unifying clearance kinetics, shape-index elevation, and topological disorder as projections of a single mechanism, with implications for understanding early-stage cancer progression.