To differentiate or not — routes towards metastasis

Why are many metastases differentiated? This Opinion article proposes that this is due to phenotypic plasticity involving transient epithelial–mesenchymal transition (EMT). In undifferentiated metastasis, it might be that cells are genetically locked into an undifferentiated state. The therapeutic consequences of this hypothesis are also discussed. Why are many metastases differentiated? Invading and disseminating carcinoma cells can undergo an epithelial–mesenchymal transition (EMT), which is associated with a gain of stem cell-like behaviour. Therefore, EMT has been linked to the cancer stem cell concept. However, it is a matter of debate how subsequent mesenchymal–epithelial transition (MET) fits into the metastatic process and whether a MET is essential. In this Opinion article, I propose two principle types of metastatic progression: phenotypic plasticity involving transient EMT–MET processes and intrinsic genetic alterations keeping cells in an EMT and stemness state. This simplified classification integrates clinically relevant aspects of dormancy, metastatic tropism and therapy resistance, and implies perspectives on treatment strategies against metastasis.