Abstract A013: Loss of MLL3 epigenetic regulator drives metastasis by promoting a hybrid epithelial-mesenchymal transition state

Abstract Phenotypic plasticity associated with the hybrid epithelial-mesenchymal transition (EMT) state is crucial to metastatic seeding and outgrowth. However, the mechanisms controlling the induction of hybrid EMT remain poorly defined. 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 mesenchymal-epithelial transition, respectively, distinct from other known EMT regulators mediating unidirectional changes. Consequently, MLL3 deletion greatly increased metastasis by enhancing metastatic colonization. MLL3 loss led to increased IFNg signaling, which is required for the induction of hybrid EMT cells and the enhanced metastatic capacity. Mechanically, MLL3 loss enhanced IFNg signaling by increasing H3K27ac intensity in the enhancers of a subset of IFNg response genes in both epithelial and mesenchymal tumor cells. We further showed that MLL3-deficient cells were sensitive to BET inhibition, which effectively suppressed the growth of MLL3-mutant primary tumors and metastases. These results uncovered a key driver of the hybrid EMT state in breast cancer that could be targeted therapeutically. Citation Format: Jihong Cui, Chi Zhang, Ji-Eun Lee, Boris Bartholdy, Dapeng Yang, Yu Liu, Piril Erler, Phillip Galbo, Dayle Q. Hodge, Danwei Huangfu, Deyou Zheng, Kai Ge, Wenjun Guo. Loss of MLL3 epigenetic regulator drives metastasis by promoting a hybrid epithelial-mesenchymal transition state [abstract]. In: Proceedings of the AACR Special Conference: Cancer Metastasis; 2022 Nov 14-17; Portland, OR. Philadelphia (PA): AACR; Cancer Res 2022;83(2 Suppl_2):Abstract nr A013.