Acquisition of cancer stem cell properties during EMT requires cell division

Cancer cells acquire stem cell and mesenchymal properties during epithelial-to-mesenchymal transition (EMT), facilitating metastasis and chemoresistance [1-6]. In this study, we find that mammary epithelial cells quickly develop mesenchymal phenotype in response to EMT-inducing signals; however, acquiring stemness takes several days and always requires a preceding mesenchymal program. In addition, we observe that carcinoma cells, over a period of time, switch their cell division from symmetrical differentiated type to symmetrical self-renewal type. Importantly, epithelial cells can gain mesenchymal properties without undergoing cell division, but cell disivion is vital for these cells to gain stem cell properties during EMT. The EMT-induced stemness signature (SC-sig) is capable of predicting progression-free and overall-survival of breast cancer patients but not the EMT-induced mesenchymal signature (M-sig). Collectively, our findings demonstrate that the use of mesenchymal markers alone is insufficient to identify tumors with metastatic and chemoresistance potential and emphasize that the markers of EMT-induced stem cell program are central for clinical prediction. Most importantly, our data, for the first time, demonstrate that acquisition of stem cell properties during EMT depends on cell division but not the mesenchymal program.