Therapeutic induction of mesenchymal-epithelial transition via epigenetic reprogramming curtails metastatic progression and sensitizes breast cancers to treatment [CUT&RUN-mouse]

The epithelial-mesenchymal transition (EMT) is a developmental program that is co-opted by tumor cells to aid in their embarking on the metastatic cascade. Tumor cells that undergo EMT are known to be endowed by, amongst other traits, heightened resistance to chemotherapy. Despite a clear understanding of the role played by the EMT program in conferring cells with these aggressive traits, there are currently no therapeutic avenues specifically targeting the program. Here we show that treatment of mesenchymal-like breast cancer cells with eribulin, an FDA-approved drug for the treatment of advanced breast cancers, leads to a mesenchymal-epithelial transition (MET), accompanied by a loss of metastatic propensity and sensitization of tumor cells to subsequent rounds of chemotherapy. We uncover a novel alternate mechanism of action that provides evidence for eribulin pretreatment as a viable clinical mechanism of MET induction that curtails metastatic progression and the evolution of therapy resistance. Overall design: CUT&RUN. PB3 cells were treated with 300nM eribulin for 24, 48, and 72h. Paired-end RNA-sequencing of two replicates per cell line.