MLL3 Loss Drives Metastasis by Promoting a Hybrid Epithelial-Mesenchymal Transition State [ATAC-seq]

Phenotypic plasticity associated with the hybrid epithelial-mesenchymal transition (EMT) state is crucial to metastatic seeding and outgrowth. We showed that deletion of the epigenetic regulator MLL3, a tumor suppressor frequently altered in human cancer, promoted the acquisition of the hybrid EMT state in both epithelial and mesenchymal breast cancer cells by facilitating EMT and MET, distinct from other known EMT regulators mediating unidirectional changes. MLL3 deletion greatly increased metastasis by enhancing metastatic outgrowth during colonization. Mechanistically, MLL3 loss led to IFNγ signaling upregulation, which contributes to the induction of hybrid EMT cells and the enhanced metastatic capacity. We treated the WT and MLL3-mutant MDA-MB-231 cells with forskolin for 14 days and used flow cytometry to isolate CD44+CD104high hybrid EMT and CD44+CD104low mesenchymal tumor cells. ATAC-Seq was performed using sorted cells in 2 replicates.