Mesenchymal to Epithelial Transition (MET) in Cancer Progression: Insights from logical modeling

The ability of carcinoma cells to transition along the epithelial-mesenchymal spectrum is crucial for metastasis. While the process of Epithelial to Mesenchymal Transition (EMT) has widely been studied, its reverse, Mesenchymal to Epithelial Transition (MET), has been less thoroughly explored. Here, we first present a comprehensive overview of the known MET inducers in cancer, detailing the cellular contexts in which they play a role and their interactions with EMT drivers. Based on these observations, we constructed a minimal regulatory network centered on key signaling pathways, including Transforming Growth Factor β (TGF β ), Bone morphogenetic protein (BMP), and other growth factors. This network was then translated into a logical model to explore the dynamic interplay between EMT and MET programs. Through in silico simulations, we demonstrate how perturbing this network can interfere with EMT programs to induce MET. Our findings highlight that the MET process is highly dependent on the mesenchymal context. We further demonstrate that persistence of EMT programs constrains how far along the epithelial–mesenchymal spectrum different MET inducers can reposition mesenchymal cells. Moreover, perturbing components of one EMT program can reinforce alternative EMT pathways, thereby preserving this balance and preventing a full reversion to epithelial states, highlighting a new function for cells with transitive states.