Abstract
Epithelial-to-mesenchymal transition (EMT) has been associated with cancer cell heterogeneity, plasticity, and metastasis. However, the extrinsic signals supervising these phenotypic transitions remain elusive. To assess how selected microenvironmental signals control cancer-associated phenotypes along the EMT continuum, we defined a logical model of the EMT cellular network that yields qualitative degrees of cell adhesions by adherens junctions and focal adhesions, two features affected during EMT. The model attractors recovered epithelial, mesenchymal, and hybrid phenotypes. Simulations showed that hybrid phenotypes may arise through independent molecular paths involving stringent extrinsic signals. Of particular interest, model predictions and their experimental validations indicated that: (i) stiffening of the extracellular matrix was a prerequisite for cells overactivating FAK_SRC to upregulate SNAIL and acquire a mesenchymal phenotype and (ii) FAK_SRC inhibition of cell-cell contacts through the receptor-type tyrosine-protein phosphatases kappa led to acquisition of a full mesenchymal, rather than a hybrid, phenotype. Altogether, these computational and experimental approaches allow assessment of critical microenvironmental signals controlling hybrid EMT phenotypes and indicate that EMT involves multiple molecular programs. SIGNIFICANCE: A multidisciplinary study sheds light on microenvironmental signals controlling cancer cell plasticity along EMT and suggests that hybrid and mesenchymal phenotypes arise through independent molecular paths.
Highlights
Metastasis is a hallmark of cancer and the leading cause of mortality among patients with cancer
The model accounts for the phenotypic repertoire identified using experimental and mathematical modeling assessments of Epithelial-to-mesenchymal transition (EMT) [7, 9, 36, 37], including pure epithelial (E1) and mesenchymal (M) phenotypes, as well as hybrid phenotypes (H)
The ease by which these hybrid phenotypes evolve upon microenvironmental stimulations could reflect the observed pluripotent abilities of cancer cells in these hybrid states [2]
Summary
Metastasis is a hallmark of cancer and the leading cause of mortality among patients with cancer. Despite intensive effort in basic and clinical research, metastatic cancers still present a major barrier to favorable clinical outcomes [1]. The fight against cancer calls for a better understanding of the involved cellular mechanisms. The progression from carcinoma to metastatic cancer has been proposed to involve a shift from an epithelial to a mesenchymal phenotype, in a highly plastic and dynamic process referred to as. Note: Supplementary data for this article are available at Cancer Research Online (http://cancerres.aacrjournals.org/).
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