Cell plasticity represents the ability of cells to undergo dynamic, non-genetic transitions between cell states. For cancer cells, this manifests as the ability to acquire cell states that aid in their survival that contributes to every step of tumour progression. This plasticity also contributes to the heterogeneity observed in particularly aggressive subtypes of breast cancer, such as triple-negative breast cancer (TNBC), complicating the development of effective targeted treatments. We propose that targeting the molecular programmes regulating cancer cell plasticity itself represents a novel strategy to tackle the biggest obstacles to successful therapies; metastasis and resistance.
We have previously shown that ZEB1 is a major driver of TNBC cell plasticity, driving the emergence of metastatic, chemoresistant cells. Indeed, numerous studies have shown that inhibiting ZEB1 reduces metastasis and sensitised cancer cells to standard therapies. Unfortunately, ZEB1 is currently undruggable. We propose that uncovering the molecular mechanisms of ZEB1-mediated plasticity in TNBC will advance research efforts to target ZEB1 therapeutically and tackle the aggressive properties of the disease.
Our data is the first to address that ZEB1 is expressed as multiple proteoforms, spanning 124 – 260kDa, that have distinct subcellar localisations and functions. In addition, preliminary proteomics data indicates novel functions of ZEB1 beyond its role as a transcription factor, involved in processes such as metabolism, translation and cytoskeletal organisation. This highlights the potential multi-faceted mechanisms by which ZEB1 drives cell state changes beyond the EMT. Further analysis of the specific PTMs regulating these functions can guide research efforts to target ZEB1.