Plasticity between Epithelial and Mesenchymal States Unlinks EMT from Metastasis-Enhancing Stem Cell Capacity

Publication date: Available online 3 March 2016
Source:Cell Reports
Author(s): Evelyne Beerling, Daniëlle Seinstra, Elzo de Wit, Lennart Kester, Daphne van der Velden, Carrie Maynard, Ronny Schäfer, Paul van Diest, Emile Voest, Alexander van Oudenaarden, Nienke Vrisekoop, Jacco van Rheenen
Forced overexpression and/or downregulation of proteins regulating epithelial-to-mesenchymal transition (EMT) has been reported to alter metastasis by changing migration and stem cell capacity of tumor cells. However, these manipulations artificially keep cells in fixed states, while in vivo cells may adapt transient and reversible states. Here, we have tested the existence and role of epithelial-mesenchymal plasticity in metastasis of mammary tumors without artificially modifying EMT regulators. In these tumors, we found by intravital microscopy that the motile tumor cells have undergone EMT, while their epithelial counterparts were not migratory. Moreover, we found that epithelial-mesenchymal plasticity renders any EMT-induced stemness differences, as reported previously, irrelevant for metastatic outgrowth, because mesenchymal cells that arrive at secondary sites convert to the epithelial state within one or two divisions, thereby obtaining the same stem cell potential as their arrived epithelial counterparts. We conclude that epithelial-mesenchymal plasticity supports migration but additionally eliminates stemness-enhanced metastatic outgrowth differences.

Graphical abstract

Teaser

Beerling et al. identified a previously undetectable pool of cells in epithelial breast tumors that have undergone EMT without experimental induction. These cells are motile when disseminating and revert back to the epithelial state upon metastatic outgrowth. This epithelial-mesenchymal plasticity equalizes metastatic outgrowth potential between epithelial and mesenchymal tumor cells.


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