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• W2277996852 abstract "Epithelial to mesenchymal transition (EMT) is an essential differentiation program during tissue morphogenesis and remodeling. EMT is induced by soluble transforming growth factor β (TGF-β) family members, and restricted by vascular endothelial growth factor fam- ily 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 TGF-β induced EMT to better understand the operational hierarchy of this complex molecular pro- gram. 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. TGF-β exposure drove the model population toward a mesenchymal phenotype, while an epithelial phenotype was enhanced following vascular endothelial growth factor A (VEGF- A) exposure. Simulations predicted that the transcription factors phosphorylated SP1 and NFAT were master regulators promoting or inhibiting EMT, respectively. Surprisingly, simulations also predicted that a cellular population could exhibit phenotypic heterogene- ity (characterized by a significant fraction of the population with both high epithelial and mesenchymal marker expression) if treated simultaneously with TGF-β and VEGF-A. We tested this prediction experimentally in both MCF10A and DLD1 cells and found that up- wards of 45% of the cellular population acquired this hybrid state in the presence of both TGF-β and VEGF-A. We experimentally validated the predicted NFAT/Sp1 signaling axis for each phenotype response. Lastly, we found that cells in the hybrid state had signifi- cantly different functional behavior when compared to VEGF-A or TGF-β treatment alone. Together, these results establish a predictive mechanistic model of EMT susceptibility, and potentially reveal a novel signaling axis which regulates carcinoma progression through an EMT versus tubulogenesis response." @default.
• W2277996852 created "2016-06-24" @default.
• W2277996852 creator A5003161155 @default.
• W2277996852 creator A5008887268 @default.
• W2277996852 creator A5020079717 @default.
• W2277996852 creator A5060963014 @default.
• W2277996852 date "2015-10-13" @default.
• W2277996852 modified "2023-09-25" @default.
• W2277996852 title "Population heterogeneity in the epithelial to mesenchymal transition is controlled by NFAT and phosphorylated Sp1" @default.
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