Abstract

Abstract:

We have shown, that in particular tumor cells at the invasive front undergo a partial epithelial-mesenchymal transition (EMT) and aberrantly express EMT -associated transcription factors (EMT-TFs). The amount of such cancer cells strongly correlates with metastasis formation and poor clinical outcome in human cancers. Strikingly, metastases show a mesenchymal-epithelial re-transition (MET) with a re-differentiated phenotype, indicating high cancer cell plasticity and supporting a regulatory role of the tumor environment. We described that the EMT -TF ZEB1 is a crucial determinant of cellular plasticity. At molecular level, ZEB1 is linked in a double negative feedback loop with the miR-200 family and miR-203, which are strong inducers of epithelial differentiation. Thus aberrant ZEB1 expression stabilizes EMT and stemness, thereby promoting dissemination, metastasis and drug resistance of cancer cells. We have validated the findings, by showing that a depletion of ZEB1 in the KPC -mouse model of pancreatic cancer counteracts tumor cell plasticity and metastasis. Moreover we detected that ZEB1 controls the Notch pathway and directly cooperates with the Hippo-pathway effector YAP in driving aggressive cancer types. We determined epigenetic modifications conferred by ZEB1 , screened for epigenetic drug to restore expression of its silenced target genes and to subsequently overcome therapy resistance. Despite their potent tumor-promoting effects, EMT -TFs are rarely mutated in cancer. This likely due to the necessity for a transient expression and the associated plasticity of cancer cells, underscoring the important role of non-mutated genes in cancer progression.