Anti-social cells: Predicting the influence of E-cadherin loss on the growth of epithelial cell populations

Abstract

Abstract The characteristics of biological tissues are determined by the interactions of large numbers of autonomous cells. These interactions can be mediated remotely by diffusive biochemical factors, or by direct cell-cell contact. E-cadherin is a protein expressed on the surface of normal epithelial cells that plays a key role in mediating intercellular adhesion via calcium-dependent homotypic interactions. E-cadherin is a metastasis-suppressor protein and its loss of function is associated with malignant progression. The purpose of this study was to apply an agent-based simulation paradigm in order to examine the emergent growth properties of mixed populations consisting of normal and E-cadherin defective cells in monolayer cell culture. Specifically, we have investigated the dynamics of normal cell:cell interactions in terms of intercellular adhesion and migration, and have used a simplified rule to represent the concepts of juxtacrine Epidermal Growth Factor Receptor (EGFR) activation and subsequent effect on cell proliferation. This cellular level control determines the overall population growth in a simulated experiment. Our approach provides a tool for modeling the development of defined biological abnormalities in epithelial and other biological tissues, raising novel predictions for future experimental testing. The results predict that even a relatively small number of abnormal (‘anti-social’) cells can modify the rate of the total population expansion, but the magnitude of this effect also depends on the extrinsic (culture) environment. In addition to directly influencing population dynamics, ‘anti-social’ cells can also disrupt the behavior of the normal cells around them.