Hybrid epithelial-mesenchymal phenotypes are controlled by microenvironmental factors

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Hybrid epithelial-mesenchymal phenotypes are controlled by microenvironmental factors

Tuesday, 21.04.2020

Authors and Affiliations:

Selvaggio G1, Canato S1Pawar A1Monteiro PT2Guerreiro PS3Brás MM4Janody F1 IGC, Instituto Gulbenkian de Ciência.

2 Instituto Superior Técnico, University of Lisbon.

3 Cytoskeletal Regulation and Cancer Group, Instituto de Investigação e Inovação em Saúde, Universidade do Porto (i3S).

4 INEB - Instituto de Engenharia Biomédica, Instituto de Investigação e Inovação em Saúde.

5 Cell Biology, Instituto Gulbenkian de Ciência.

6 IGC, Instituto Gulbenkian de Ciência



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: 1) stiffening of the ExtraCellular Matrix (ECM) was a prerequisite for cells overactivating FAK_SRC to upregulate SNAIL and acquire a mesenchymal phenotype, and 2) 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.


Journal: Cancer Research