A biomechanical model for epithelial defense against cancer

Epithelial systems tightly regulate their homeostatic mechanism through an interplay between cell growth, proliferation, and death. Non-proliferative cell competition is one such established process that preferentially eliminates one cell population over another to preserve the tissue homeostasis, widely observed in the process of epithelial defense against cancer (EDAC). In this work we study in detail the contribution of tissue mechanics towards regulating non-proliferative cell competition in vitro and in silico. Using force microscopy techniques in vitro, we demonstrate that compressive stress emerges as a unique mechanical signature for competitive elimination of HRas^V12-transformed cells. Further, using a combination of biophysical techniques, we identify homeostatic pressure differential, cellular compressibility, and junctional instability as the potential candidate for the origin of compressive stress. We use cell-based physical models to uncover the relative sensitivity of these biomechanical factors towards promoting cell competition. These findings collectively establish mechanical imbalance between the competing cell populations as the cue for compaction and subsequent loser cell elimination.