Pleiotropic Roles for ZEB1 in Cancer.

ZEB1 is a prime element of a network of transcription factors that controls epithelial-to-mesenchymal transition (EMT), a reversible embryonic transdifferentiation program that allows partial or complete transition from an epithelial to a mesenchymal state. Aberrant expression of ZEB1 has been reported in a variety of human cancers, where it is generally believed to foster migration, invasion, and metastasis. Over the past few years, in vitro and in vivo observations have highlighted unsuspected intrinsic oncogenic functions of ZEB1 that impact tumorigenesis from its earliest stages. Located downstream of regulatory processes that integrate microenvironmental signals and directly implicated in feedback loops controlled by miRNAs, ZEB1 appears to be a central switch that determines cell fate. Its expression fosters malignant transformation through the mitigation of critical oncosuppressive pathways and through the conferment of stemness properties. ZEB1 is also a key determinant of cell plasticity, endowing cells with the capacity to withstand an aberrant mitogenic activity, with a profound impact on the genetic history of tumorigenesis, and to adapt to the multiple constraints encountered over the course of tumor development. Cancer Res; 78(1); 30-35. ©2017 AACR.

ZEB1-mediated melanoma cell plasticity enhances resistance to MAPK inhibitors.

Targeted therapies with MAPK inhibitors (MAPKi) are faced with severe problems of resistance in BRAF-mutant melanoma. In parallel to the acquisition of genetic mutations, melanoma cells may also adapt to the drugs through phenotype switching. The ZEB1 transcription factor, a known inducer of EMT and invasiveness, is now considered as a genuine oncogenic factor required for tumor initiation, cancer cell plasticity, and drug resistance in carcinomas. Here, we show that high levels of ZEB1 expression are associated with inherent resistance to MAPKi in BRAFV600-mutated cell lines and tumors. ZEB1 levels are also elevated in melanoma cells with acquired resistance and in biopsies from patients relapsing while under treatment. ZEB1 overexpression is sufficient to drive the emergence of resistance to MAPKi by promoting a reversible transition toward a MITFlow/p75high stem-like and tumorigenic phenotype. ZEB1 inhibition promotes cell differentiation, prevents tumorigenic growth in vivo, sensitizes naive melanoma cells to MAPKi, and induces cell death in resistant cells. Overall, our results demonstrate that ZEB1 is a major driver of melanoma cell plasticity, driving drug adaptation and phenotypic resistance to MAPKi.