Biology

Mohit Kumar Jolly
Rice University, Houston, TX, USA

Epithelial-Mesenchymal Transition (EMT) and its reverse Mesenchymal-to-Epithelial Transition (MET) are fundamental biological phenomena that play crucial roles during embryonic development, wound healing, and cancer metastasis. Cells undergoing EMT shed their cell-cell adhesion and gain migration and invasion; those undergoing MET regain cell-cell adhesion while losing migration and invasion. Despite remarkable progress in charting the molecular players that regulate EMT/MET, the underlying principles of these transitions remain elusive. We mathematically modeled the core EMT/MET genetic circuit composed of two interlinked double negative feedback loops – one between miR-34 and SNAIL, and the other between miR-200 and ZEB. Our model predicted that while miR-34/SNAIL loop acted as a noise-buffering integrator, the miR-200/ZEB loop acted as a three-way switch enabling three phenotypes – epithelial, mesenchymal, and hybrid epithelial/mesenchymal (E/M). Further, the model predicted that transcription factors OVOL and GRHL2 can maintain cells in a hybrid E/M phenotype that can enable collective migration. These predictions were validated experimentally in H1975 lung cancer cells that are stably in a hybrid E/M phenotype and migrate collectively until OVOL and GRHL2 are knocked down. Finally, based on experimental data from RD and 143B sarcoma (mesenchymal cancers) cells, we infer that the coupling of GRHL2 with miR-200/ZEB is different in sarcomas as compared to carcinomas (epithelial cancers), indicating a different epigenetic regulation of EMT in different tissues. Our integrated theoretical-experimental approach elucidates the principles of transcriptional, translational, and epigenetic regulation of EMT, and suggests that the tacit assumption that hybrid E/M is a ‘metastable’ or transient state need not be always true; instead cells can stably attain a hybrid E/M phenotype.