A Dimension Reduction Approach for Energy Landscape: Identifying Intermediate States in Metabolism‐EMT Network

Dimension reduction is a challenging problem in complex dynamical systems. Here, a dimension reduction approach of landscape (DRL) for complex dynamical systems is proposed, by mapping a high-dimensional system on a low-dimensional energy landscape. The DRL approach is applied to three biological networks, which validates that new reduced dimensions preserve the major information of stability and transition of original high-dimensional systems. The consistency of barrier heights calculated from the low-dimensional landscape and transition actions calculated from the high-dimensional system further shows that the landscape after dimension reduction can quantify the global stability of the system. The epithelial-mesenchymal transition (EMT) and abnormal metabolism are two hallmarks of cancer. With the DRL approach, a quadrastable landscape for metabolism-EMT network is identified, including epithelial (E), abnormal metabolic (A), hybrid E/M (H), and mesenchymal (M) cell states. The quantified energy landscape and kinetic transition paths suggest that for the EMT process, the cells at E state need to first change their metabolism, then enter the M state. The work proposes a general framework for the dimension reduction of a stochastic dynamical system, and advances the mechanistic understanding of the underlying relationship between EMT and cellular metabolism.