UNASSIGNED: Epithelial to mesenchymal transition (EMT) is an essential differentiation program during tissue morphogenesis and remodeling. EMT is induced by soluble @entity2533 ( @entity2533 ) family members, and restricted by vascular endothelial growth factor family members. While many downstream molecular regulators of EMT have been identified, these have been largely evaluated individually without considering potential crosstalk. In this study, we created an ensemble of dynamic mathematical models describing @entity2533 induced EMT to better understand the operational hierarchy of this complex molecular program. We used ordinary differential equations (ODEs) to describe the transcriptional and post-translational regulatory events driving EMT. Model parameters were estimated from multiple data sets using multiobjective optimization, in combination with cross-validation. @entity2533 exposure drove the model population toward a mesenchymal phenotype, while an epithelial phenotype was enhanced following @entity7 ( @entity7 ) exposure. Simulations predicted that the transcription factors phosphorylated @entity3419 and NFAT were master regulators promoting or inhibiting EMT, respectively. Surprisingly, simulations also predicted that a cellular population could exhibit phenotypic heterogeneity (characterized by a significant fraction of the population with both high epithelial and mesenchymal marker expression) if treated simultaneously with @entity2533 and @entity7 . We tested this prediction experimentally in both MCF10A and DLD1 cells and found that upwards of 45% of the cellular population acquired this hybrid state in the presence of both @entity2533 and @entity7 . We experimentally validated the predicted NFAT/ @entity3419 signaling axis for each phenotype response. Lastly, we found that cells in the hybrid state had significantly different functional behavior when compared to @entity7 or @entity2533 treatment alone. Together, these results establish a predictive mechanistic model of EMT susceptibility, and potentially reveal a novel signaling axis which regulates @entity189 progression through an EMT versus tubulogenesis response.

Population Heterogeneity in the Epithelial to Mesenchymal Transition Is Controlled by NFAT and Phosphorylated XXXX .

@entity2533 :: ('7040', 'Gene') :: ['TGF-b', 'transforming growth factor b'] @entity189 :: ('MESH:D002277', 'Disease') :: ['carcinoma'] @entity3419 :: ('6667', 'Gene') :: ['Sp1', 'SP1'] @entity7 :: ('7422', 'Gene') :: ['VEGF-A', 'vascular endothelial growth factor A']
@entity3419 :: (6667,Gene) :: ['Sp1']
