Energy Landscape Analysis of the Epithelial-Mesenchymal Transition Network

Abstract

The epithelial-mesenchymal transition (EMT) is a key developmental program that is often activated during the cancer invasion, metastasis, and drug resistance. However, it remains a critical question to elucidate the mechanisms of EMT. For example, how to quantify the global stability and stochastic transition dynamics of EMT under fluctuations is yet to be clarified. Here, we describe a framework and detailed steps for stochastic dynamics analysis of EMT. Starting from the underlying EMT gene regulatory network, we quantify the energy landscape of the EMT computationally. Multiple steady-state attractors are identified on the landscape surface, characterizing different cell phenotypes. The kinetic transition paths based on large deviation theory delineate the transition processes between different attractors quantitatively. The EMT or the reverse process, the mesenchymal-epithelial transition (MET), can be achieved by either a direct transition or a step-wise transition that goes through an intermediate state, depending on different extracellular environments. The landscape and transition paths presented in this chapter provide a new physical and quantitative picture to understand the underlying mechanisms of the EMT process. The approach for landscape and path analysis can be extended to other biological networks.

Keywords: Energy landscape; Epithelial–mesenchymal transition; Gene regulatory network; Intermediate states; Mathematical models; Transition path.