A cell’s phenotype is the set of observable characteristics resulting from the interaction of the genotype with the surrounding environment, determining cell behaviour. Deciphering genotype-phenotype relationships has been crucial to understand normal and disease biology. Analysis of molecular pathways has provided an invaluable tool to such understanding; however, it does typically not consider the physical microenvironment, which is a key determinant of phenotype. In this study, we present a novel modelling framework that enables to study the link between genotype, signalling networks and cell behaviour in a 3D microenvironment. To achieve this we bring together Agent Based Modelling, a powerful computational modelling technique, and gene networks. This combination allows biological hypotheses to be tested in a controlled stepwise fashion, and it lends itself naturally to model a heterogeneous population of cells acting and evolving in a dynamic microenvironment, which is needed to predict the evolution of complex multi-cellular dynamics. Importantly, this enables modelling co-occurring intrinsic perturbations, such as mutations, and extrinsic perturbations, such as nutrients availability, and their interactions. Using cancer as a model system, we illustrate the how this framework delivers a unique opportunity to identify determinants of single-cell behaviour, while uncovering emerging properties of multi-cellular growth.
