Modeling the dynamics of EMT reveals genes associated with pan-cancer intermediate states and plasticity.

Abstract

Epithelial-mesenchymal transition (EMT) is a cell state transition co-opted by cancer that drives metastasis via stable intermediate states. Here we study EMT dynamics to identify marker genes of highly metastatic intermediate cells via mathematical modeling with single-cell RNA sequencing (scRNA-seq) data. Across multiple tumor types and stimuli, we identified genes consistently upregulated in EMT intermediate states, many previously unrecognized as EMT markers. Bayesian parameter inference of a simple EMT mathematical model revealed tumor-specific transition rates, providing a framework to quantify EMT progression. Consensus analysis of differential expression, RNA velocity, and model-derived dynamics highlighted SFN and NRG1 as key regulators of intermediate EMT. Independent validation confirmed SFN as an intermediate state marker. Our approach integrates modeling and inference to identify genes associated with EMT dynamics, offering biomarkers and therapeutic targets to modulate tumor-promoting cell state transitions driven by EMT.