A plausible accelerating function of intermediate states in cancer metastasis

Epithelial-to-mesenchymal transition (EMT) is a fundamental cellular process and plays an essential role in development, tissue regeneration, and cancer metastasis. Interestingly, EMT is not a binary process but instead proceeds with multiple partial intermediate states. However, the functions of these intermediate states are not fully understood. Here, we focus on a general question about how the number of partial EMT states affects cell transformation. First, by fitting a hidden Markov model of EMT with experimental data, we propose a statistical mechanism for EMT in which many unobservable microstates may exist within one of the observable macrostates. Furthermore, we find that increasing the number of intermediate states can accelerate the EMT process and that adding parallel paths or transition layers may accelerate the process even further. Last, a stabilized intermediate state traps cells in one partial EMT state. This work advances our understanding of the dynamics and functions of EMT plasticity during cancer metastasis.Author summary: Epithelial-mesenchymal transition (EMT) is a basic biological process, in which epithelial cells undergo multiple biochemical changes, lose cell-cell junctions and polarization, and become a mesenchymal phenotype with migratory and invasive properties. Recent studies have illustrated the existence and importance of the partial EMT states. It has become increasingly apparent that the EMT has strong differentiation plasticity. This plasticity is heavily implicated in cancer cell invasion and metastasis. However, it is still unclear how the number of intermediate states changes the EMT process. Here, we use a hidden Markov model to describe the EMT process. By fitting with the experimental data, we find that unobservable microstates exist within the observable macrostates: epithelial, partial EMT, and mesenchymal. Additionally, we find that increasing the number of states between the start and end of EMT or including alternative transition avenues via parallel paths or transition layers can accelerate the EMT process. This study suggests a non-trivial function of the EMT plasticity during cancer metastasis.