Modelling genotypes in their microenvironment to predict single- and multi-cellular behaviour

<jats:title>ABSTRACT</jats:title><jats:p>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.</jats:p><jats:p>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.</jats:p><jats:p>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.</jats:p><jats:sec><jats:title>Availability and Implementation</jats:title><jats:p>Freely available on the web at <jats:ext-link xmlns:xlink="http://www.w3.org/1999/xlink" ext-link-type="uri" xlink:href="http://www.microc.org">http://www.microc.org</jats:ext-link>. Research Resource Identification Initiative ID (<jats:ext-link xmlns:xlink="http://www.w3.org/1999/xlink" ext-link-type="uri" xlink:href="https://scicrunch.org/">https://scicrunch.org/</jats:ext-link>): SCR 016672</jats:p></jats:sec>