Hybrid Epithelial-Mesenchymal Phenotypes Are Controlled by Microenvironmental Factors

Area of Science:

• Cell Biology
• Cancer Research
• Computational Biology

Background:

• Epithelial-to-mesenchymal transition (EMT) drives cancer cell heterogeneity, plasticity, and metastasis.
• Extrinsic signals governing these EMT-associated phenotypic transitions are not fully understood.

Purpose of the Study:

• To investigate how specific microenvironmental signals regulate cancer cell phenotypes along the EMT spectrum.
• To model the EMT cellular network and identify key molecular pathways.

Main Methods:

• Development of a logical model of the EMT cellular network to simulate cell adhesion properties.
• Computational simulations to predict epithelial, mesenchymal, and hybrid phenotypes.
• Experimental validation of model predictions regarding microenvironmental influences.

Main Results:

• Model attractors successfully identified epithelial, mesenchymal, and hybrid phenotypes.
• Hybrid phenotypes can emerge via independent molecular routes driven by specific extrinsic signals.
• Extracellular matrix stiffening and FAK-SRC activation are prerequisites for mesenchymal phenotype acquisition.
• FAK-SRC inhibition of cell-cell contacts promotes a full mesenchymal phenotype over a hybrid one.

Conclusions:

• Computational and experimental methods elucidated critical microenvironmental signals controlling hybrid EMT phenotypes.
• EMT involves multiple, distinct molecular programs.
• Hybrid and full mesenchymal phenotypes arise through independent molecular pathways.