The Clinical Relevance of Epithelial-to-Mesenchymal Transition Hallmarks: A Cut-Off-Based Approach in Healthy and Cancerous Cell Lines

The atypical activation of the epithelial-to-mesenchymal transition represents one of the main mechanisms driving cancer cell dissemination. It enables epithelial cancer cells to detach from the primary tumor mass and gain survival advantages in the bloodstream, significantly contributing to the spread of circulating tumor cells. Notably, epithelial-to-mesenchymal transition is not a binary process but rather leads to the formation of a wide range of cell subpopulations characterized by the simultaneous expression of both epithelial and mesenchymal markers. Therefore, analyzing the modulation of EMT hallmarks during the conversion from healthy cells to metastatic cancer cells, which acquire stem mesenchymal characteristics, is of particular interest. This study investigates the expression of a panel of epithelial-to-mesenchymal transition-related genes in healthy cells, primary and metastatic cancer cells, and in mesenchymal cell lines, derived from various tissues, including the lung, colon, pancreas, skin, and neuro-ectoderm, with the aim of identifying potential cut-off values for assessing cancer aggressiveness. Interestingly, we found that the expression levels of CDH1, which encodes the epithelial marker E-cadherin, CDH5, encoding vascular endothelial cadherin, and the epithelial-to-mesenchymal transition-transcription factor ZEB1, effectively distinguished primary from metastatic cancer cells. Additionally, our data suggest a tissue-specific signature in the modulation of epithelial-to-mesenchymal transition markers during cancer progression. Overall, our results underscore the importance of investigating epithelial-to-mesenchymal transition as a tissue-specific process to identify the most suitable markers acting as potential indicators of disease aggressiveness and therapeutic responsiveness.