Modulation of steady-state and transition dynamics of EMT by extra- and intracellular signaling crosstalk

Epithelial–mesenchymal transition (EMT) is a fundamental cellular program that enables epithelial cells to acquire mesenchymal properties, playing key roles in development, tissue repair, and cancer progression. In tumors, EMT contributes to metastasis, therapy resistance, and cellular plasticity, often through intermediate, reversible hybrid states. These transitions are controlled by a complex regulatory network centered on transcription factors such as Snail1 and Zeb1, which are tightly regulated by microRNAs and epigenetic modifications. Moreover, extracellular signals like TGF𝛽 dynamically influence EMT behavior through extensive signaling crosstalk.

This project aims to uncover how intracellular regulatory circuits and extracellular signals jointly control the dynamics and stability of EMT and its reverse process, MET. By combining mathematical modeling with quantitative experiments in breast epithelial cells, we investigate how epigenetic regulation, network interactions, and signaling crosstalk shape cellular decision-making and phenotypic heterogeneity. A particular focus lies on understanding how perturbations such as DNA methylation of key microRNAs or alterations in tumor suppressors like DLC1 affect the balance between
epithelial, mesenchymal, and hybrid states.

Our approach integrates mechanistic modeling with experimental data to systematically analyze TGF𝛽-induced EMT at three levels: (i) modifications within the core regulatory network, (ii) interactions with additional molecular components, and (iii) coupling to extracellular signaling pathways such as MAPK and TNF𝛼. This allows us to dissect how
feedback and feedforward motifs give rise to multistability and dynamic transitions between cell states.