The ability of cancer cells to undergo dynamic, non-genetic transitions between cell states is a major driver of tumour heterogeneity, metastasis, and therapy resistance. As a result, cancer cell plasticity represents one of the biggest obstacles to the successful treatment of patients. Furthering our understanding the molecular mechanisms that regulate cancer cell plasticity is therefore pivotal to designing novel strategies to inhibit this complex process.
We and others have previously shown that ZEB1 is a major driver of cancer cell plasticity. Indeed, numerous studies have shown that inhibiting ZEB1 reduces metastasis and stem-like features and sensitises cancer cells to not only radio- and chemotherapy, but also targeted therapies such as immunotherapy. Most of these studies have attributed ZEB1’s role in regulating phenotypic plasticity to its canonical function as an epithelial-to-mesenchymal-transition (EMT)-transcription factor (TF). However, our previous data suggested ZEB1 may have additional functions outside of its canonical role as a TF. To explore how these may contribute ZEB1’s role in driving cancer cell plasticity, we aimed to understand how ZEB1 is regulated in triple-negative breast cancer (TNBC), a particularly aggressive and heterogenous subtype of breast cancer.
Our data is the first to address that ZEB1 is expressed as multiple proteoforms, spanning 124 – 260 kDa, that have distinct subcellar localisations and functions. ZEB1 CUT&RUN data highlights ZEB1 as a transcriptional regulator of not just EMT, but metabolism, mitosis and translation. Preliminary proteomics data also indicates novel functions of ZEB1 beyond its role as a transcription factor, supporting recent literature. Further analysis of the specific post-translational modifications regulating these functions can guide research efforts to target ZEB1. These data highlight the potential multi-faceted mechanisms by which ZEB1 drives cell state changes beyond the EMT. This will have large implications for how we perceive ‘EMT-TFs’ in the field.