EMT-induced stem cell and mesenchymal programs can be decoupled via cell division and ESRP1-dependent mechanisms

Epithelial-to-mesenchymal transition (EMT) is known to induce both stemness and mesenchymal properties, and our findings reveal that these two programs can be uncoupled. During EMT, epithelial cells transition from symmetric divisions producing differentiated daughter cells to self-renewing daughter cells. When we block cell division and induce EMT, cells gain mesenchymal properties but not stemness, suggesting the importance of cell division for gaining stemness. We identified ESRP1 as a key regulator of EMT-driven stemness, which get downregulated during EMT in a cell division-dependent manner. Overexpression of ESRP1 prevents the gain of stemness without affecting the mesenchymal program. Only the stemness and not the mesenchymal signature, induced during EMT, correlates with poor prognosis. All cancer cells with stemness properties exhibit mesenchymal properties, but not all mesenchymal cells exhibit stemness properties. In summary, during EMT the stemness program is controlled by cell division and ESRP1, and this program predicts poor prognosis.