Landscape of Epithelial Mesenchymal Plasticity as an emergent property of coordinated teams in regulatory networks

Abstract

AbstractElucidating the principles of cellular decision-making is of fundamental importance. These decisions are often orchestrated by underlying regulatory networks. While we understand the dynamics of simple network motifs, how do large networks lead to a limited number of phenotypes, despite their complexity, remains largely elusive. Here, we investigate five different networks governing epithelial-mesenchymal plasticity and identified a latent design principles in their topology that limits their phenotypic repertoire – the presence of two “teams” of nodes engaging in a mutually inhibitory feedback loop, forming a toggle switch. These teams are specific to these networks and directly shape the phenotypic landscape and consequently the frequency and stability of terminal phenotypes vs. the intermediary ones. Our analysis reveals that network topology alone can contain information about phenotypic distributions it can lead to, thus obviating the need to simulate them. We unravel topological signatures that can drive canalization of cell-fates during diverse decision-making processes.