TY - JOUR T1 - Distinguishing Mechanisms Underlying EMT Tristability JF - bioRxiv DO - 10.1101/098962 SP - 098962 AU - Dongya Jia AU - Mohit Kumar Jolly AU - Satyendra C. Tripathi AU - Petra Den Hollander AU - Bin Huang AU - Mingyang Lu AU - Muge Celiktas AU - Esmeralda Ramirez-Peña AU - Eshel Ben-Jacob AU - José N. Onuchic AU - Samir M. Hanash AU - Sendurai A. Mani AU - Herbert Levine Y1 - 2017/01/01 UR - http://biorxiv.org/content/early/2017/01/06/098962.abstract N2 - Background: The Epithelial-Mesenchymal Transition (EMT) endows epithelial-looking cells with enhanced migratory ability during embryonic development and tissue repair. EMT can also be co-opted by cancer cells to acquire metastatic potential and drug-resistance. Recent research has argued that epithelial (E) cells can undergo either a partial EMT to attain a hybrid epithelial/mesenchymal (E/M) phenotype that typically displays collective migration, or a complete EMT to adopt a mesenchymal (M) phenotype that shows individual migration. The core EMT regulatory network - miR-34/SNAIL/miR-200/ZEB1 - has been identified by various studies, but how this network regulates the transitions among the E, E/M, and M phenotypes remains controversial. Two major mathematical models – ternary chimera switch (TCS) and cascading bistable switches (CBS) - that both focus on the miR-34/SNAIL/miR-200/ZEB1 network, have been proposed to elucidate the EMT dynamics, but a detailed analysis of how well either or both of these two models can capture recent experimental observations about EMT dynamics remains to be done.Results: Here, via an integrated experimental and theoretical approach, we first show that both these two models can be used to understand the two-step transition of EMT - E→E/M→M, the different responses of SNAIL and ZEB1 to exogenous TGF-β and the irreversibility of complete EMT. Next, we present new experimental results that tend to discriminate between these two models. We show that ZEB1 is present at intermediate levels in the hybrid E/M H1975 cells, and that in HMLE cells, overexpression of SNAIL is not sufficient to initiate EMT in the absence of ZEB1 and FOXC2.Conclusions: These experimental results argue in favor of the TCS model proposing that miR-200/ZEB1 behaves as a three-way decision-making switch enabling transitions among the E, hybrid E/M and M phenotypes.(EMT)Epithelial-to-mesenchymal transition(MET)Mesenchymal-to Epithelial-Transition(TCS)Ternary Chimera Switch(CBS)Cascading Bistable Switches(CTC)Circulating Tumor Cell(PSF)Phenotypic Stability Factor ER -