Reference : Loss of inter-cellular cooperation by complete epithelial-mesenchymal transition supp...
Scientific journals : Article
Life sciences : Multidisciplinary, general & others
Systems Biomedicine
Loss of inter-cellular cooperation by complete epithelial-mesenchymal transition supports favorable outcomes in basal breast cancer patients
Grosse-Wilde, Anne [> >]
Kuestner, Rolf E. [> >]
Skelton, Stephanie M. [> >]
MacIntosh, Ellie [> >]
Fouquier d'Hérouël, Aymeric mailto [University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > >]
Ertaylan, Gökhan [> >]
del Sol, Antonio [> >]
Skupin, Alexander mailto [University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) >]
Huang, Sui [> >]
Impact Journals, LLC
[en] cancer ; EMT ; single cell
[en] According to the sequential metastasis model, aggressive mesenchymal (M) metastasis-initiating cells (MICs) are generated by an epithelial-mesenchymal transition (EMT) which eventually is reversed by a mesenchymal-epithelial transition (MET) and outgrowth of life-threatening epithelial (E) macrometastases. Paradoxically, in breast cancer M signatures are linked with more favorable outcomes than E signatures, and M cells are often dispensable for metastasis in mouse models. Here we present evidence at the cellular and patient level for the cooperation metastasis model, according to which E cells are MICs, while M cells merely support E cell persistence through cooperation. We tracked the fates of co-cultured E and M clones and of fluorescent CDH1-promoter-driven cell lines reporting the E state derived from basal breast cancer HMLER cells. Cells were placed in suspension state and allowed to reattach and select an EMT cell fate. Flow cytometry, single cell and bulk gene expression analyses revealed that only pre-existing E cells generated E cells, mixed E/M populations, or stem-like hybrid E/M cells after suspension and that complete EMT manifest in M clones and CDH1-negative reporter cells resulted in loss of cell plasticity, suggesting full transdifferentiation. Mechanistically, E-M coculture experiments supported the persistence of pre-existing E cells where M cells inhibited EMT of E cells in a mutual cooperation via direct cell-cell contact. Consistently, M signatures were associated with more favorable patient outcomes compared to E signatures in breast cancer, specifically in basal breast cancer patients. These findings suggest a potential benefit of complete EMT for basal breast cancer patients.

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