MLL3 loss drives metastasis by promoting a hybrid epithelial–mesenchymal transition state Journal Article
| Authors: | Cui, J.; Zhang, C.; Lee, J. E.; Bartholdy, B. A.; Yang, D.; Liu, Y.; Erler, P.; Galbo, P. M. Jr; Hodge, D. Q.; Huangfu, D.; Zheng, D.; Ge, K.; Guo, W. |
| Article Title: | MLL3 loss drives metastasis by promoting a hybrid epithelial–mesenchymal transition state |
| Abstract: | Phenotypic plasticity associated with the hybrid epithelial–mesenchymal transition (EMT) is crucial to metastatic seeding and outgrowth. However, the mechanisms governing the hybrid EMT state remain poorly defined. Here we showed that deletion of the epigenetic regulator MLL3, a tumour suppressor frequently altered in human cancer, promoted the acquisition of hybrid EMT in breast cancer cells. Distinct from other EMT regulators that mediate only unidirectional changes, MLL3 loss enhanced responses to stimuli inducing EMT and mesenchymal–epithelial transition in epithelial and mesenchymal cells, respectively. Consequently, MLL3 loss greatly increased metastasis by enhancing metastatic colonization. Mechanistically, MLL3 loss led to increased IFNγ signalling, which contributed to the induction of hybrid EMT cells and enhanced metastatic capacity. Furthermore, BET inhibition effectively suppressed the growth of MLL3-mutant primary tumours and metastases. These results uncovered MLL3 mutation as a key driver of hybrid EMT and metastasis in breast cancer that could be targeted therapeutically. © 2023, The Author(s), under exclusive licence to Springer Nature Limited. |
| Keywords: | signal transduction; controlled study; unclassified drug; gene mutation; human cell; gene deletion; genetics; nonhuman; bone metastasis; animal cell; mouse; animal tissue; mesenchyme cell; metastasis; animal experiment; animal model; cell differentiation; pathology; cell line, tumor; breast neoplasms; gene expression regulation; cancer inhibition; lung metastasis; gene expression regulation, neoplastic; gamma interferon; histone methyltransferase; breast tumor; tumor cell line; neoplasm metastasis; epithelium cell; mesenchymal stem cell; transcription factor t bet; mesenchymal stem cells; epithelial-mesenchymal transition; epithelial mesenchymal transition; humans; human; female; article; breast cancer cell line; metastasis in breast; histone methyltransferase mll3 |
| Journal Title: | Nature Cell Biology |
| Volume: | 25 |
| Issue: | 1 |
| ISSN: | 1465-7392 |
| Publisher: | Nature Publishing Group |
| Date Published: | 2023-01-01 |
| Start Page: | 145 |
| End Page: | 158 |
| Language: | English |
| DOI: | 10.1038/s41556-022-01045-0 |
| PUBMED: | 36604594 |
| PROVIDER: | scopus |
| PMCID: | PMC10003829 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 1 March 2023 -- Source: Scopus |
Altmetric
Citation Impact
BMJ Impact Analytics
Related MSK Work