Systems-level analysis identifies IRF6 as an inhibitor of epithelial-mesenchymal transition

Epithelial-mesenchymal transition (EMT) and its reverse process mesenchymal-epithelial transition (MET) are crucial during metastasis and therapy resistance. While the dynamics and master regulators of EMT are well-studied, the transcription factors that can prevent EMT or promote MET are relatively less understood.

Here, by integrating bulk and spatial transcriptomic data analysis from cell lines and patient samples with mechanism-based dynamical modelling we identify IRF6 as a factor that strongly associates with an epithelial phenotype and is often inhibited during EMT. In vitro experiments in multiple cancer cell lines demonstrate the progression to a mesenchymal phenotype upon IRF6 knockdown, suggesting a role as an inhibitor of EMT. Finally, we observe that IRF6 expression levels correlate with worse patient survival in a subset of solid tumour types.

Our integrated computational-experimental, systems-level analysis suggests that IRF6 is frequently downregulated during EMT and can also prevent the progression towards a complete EMT, underscoring its role as an MET stabilizing factor.