Identifying inhibitors of epithelial–mesenchymal plasticity using a network topology-based approach

Abstract

AbstractMetastasis is the cause of over 90% of cancer-related deaths. Cancer cells undergoing metastasis can switch dynamically between different phenotypes, enabling them to adapt to harsh challenges, such as overcoming anoikis and evading immune response. This ability, known as phenotypic plasticity, is crucial for the survival of cancer cells during metastasis, as well as acquiring therapy resistance. Various biochemical networks have been identified to contribute to phenotypic plasticity, but how plasticity emerges from the dynamics of these networks remains elusive. Here, we investigated the dynamics of various regulatory networks implicated in Epithelial–mesenchymal plasticity (EMP)—an important arm of phenotypic plasticity—through two different mathematical modelling frameworks: a discrete, parameter-independent framework (Boolean) and a continuous, parameter-agnostic modelling framework (RACIPE). Results from either framework in terms of phenotypic distributions obtained from a given EMP network are qualitatively similar and suggest that these networks are multi-stable and can give rise to phenotypic plasticity. Neither method requires specific kinetic parameters, thus our results emphasize that EMP can emerge through these networks over a wide range of parameter sets, elucidating the importance of network topology in enabling phenotypic plasticity. Furthermore, we show that the ability to exhibit phenotypic plasticity correlates positively with the number of positive feedback loops in a given network. These results pave a way toward an unorthodox network topology-based approach to identify crucial links in a given EMP network that can reduce phenotypic plasticity and possibly inhibit metastasis—by reducing the number of positive feedback loops.