Abstract

We have shown, that in particular tumour cells at the invasive front undergo an epithelial-mesenchymal transition (EMT) and aberrantly express EMT-associated transcriptional repressors, like ZEB1. The amount of such cells strongly correlates with metastasis formation and poor clinical outcome. Strikingly, metastases show again a differentiated phenotype, indicating a mesenchymal-epithelial re-transition (MET) and a support a regulatory role of the tumour environment for malignant tumour progression.

We described that the EMT-activator ZEB1 is a crucial promoter of metastasis and demonstrated that ZEB1 inhibits expression of cell polarity factors and the microRNA-200 family, whose members are strong inducers of epithelial differentiation. These results indicate that ZEB1 triggers a microRNA-mediated feedback-loop, which stabilizes EMT and promotes dissemination of cancer cells. Moreover we detected that in addition ZEB1 is necessary for the tumour initiating capacity of pancreatic and colorectal cancer cells. ZEB1 inhibits expression of miR-200c, miR-203 and miR-183, which cooperate to suppress expression of stem cell factors, as demonstrated for the polycomb repressor Bmi1.

We propose that ZEB1 links EMT-activation and stemness-maintenance by suppressing stemness-inhibiting microRNAs and thereby is a promoter of mobile, migrating cancer stem cells. Notably, these cells also acquired a drug-resistance phenotype. Thus, targeting the ZEB1 - miR-200 feedback loop might be a promising treatment option for fatal tumours, such as pancreatic cancer.