Synergy between epithelial and mesenchymal cells in breast cancer: from mammospheres to predicting patient outcomes

Targeting breast cancer stem cells promises to eliminate the root of metastasis and recurrence and thus to eradicate the ultimate cause of cancer-related death of patients. However, the identity of epithelial cancer stem-like is still elusive; cancer stem-like and metastasis initiating cells have been described to be either epithelial (E) or mesenchymal (M), and thus their identity appears to critically depend on the context of the analyzed cell line. Here, we have studied the heterogeneous HMLER cell line to identify the relationships between epithelial and mesenchymal cells while they are differentiated and selected under suspension culture conditions. We find that CD24+/CD44- epithelial cells and CD44+/CD24- mesenchymal cells synergize in causing the proliferation of both sub-populations, increasing mammosphere production, and causing the emergence of aggressive motile cells when replated. We observed that when grown in suspension, isolated epithelial as well as isolated mesenchymal cell populations converged towards a hybrid E/M state characterized by coexpression of genes of both lineages, from population down to the single cell level. For epithelial populations convergence at the hybrid state during growth in suspension was thus achieved by proliferation of the most mesenchymal cells resembling an epithelial to mesenchymal transition at the population level. For mesenchymal populations, the hybrid state was reached by the reverse, MET, involving proliferation of the most epithelial cells in a context dependent manner.We use these findings to resolve which genes are predictive of poor outcome in primary human breast tumors. Here we show for the first time that high expression of mesenchymal genes in luminal B/epithelial tumors predicts poor outcome of patients, whereas expression of epithelial genes in basal/mesenchymal tumors predicts poor outcome and thus increased metastasis. Therefore, functional synergy between E and M cells can explain how the tumor context determines whether a minority of mesenchymal or epithelial cells can serve as metastatic stem cells. Citation Format: Anne Grosse-Wilde, Aymeric d'Herouel, Rolf Kuestner, Gokhan Ertaylan, Alexander Skupin, Sui Huang, Adrian Ozinsky. Synergy between epithelial and mesenchymal cells in breast cancer: from mammospheres to predicting patient outcomes. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1918. doi:10.1158/1538-7445.AM2014-191