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MLL3 loss drives metastasis and therapeutic resistance by promoting a hybrid EMT state

ABSTRACT: MLL3 loss drives metastasis and therapeutic resistance by promoting a hybrid EMT state

PROVIDER: PRJNA719653 | ENA |

REPOSITORIES: ENA

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MLL3 loss drives metastasis and therapeutic resistance by promoting a hybrid EMT state [RNA-seq]

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Project description: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 MET, distinct from other known EMT regulators mediating unidirectional changes. Consequently, 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.

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MLL3 loss drives metastasis and therapeutic resistance by promoting a hybrid EMT state [RNA-seq]

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MLL3 Loss Drives Metastasis by Promoting a Hybrid Epithelial-Mesenchymal Transition State [ChIP-seq UTX and MLL4]

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MLL3 Loss Drives Metastasis by Promoting a Hybrid Epithelial-Mesenchymal Transition State [RNA-seq MDA231 KO vs WT]

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MLL3 loss drives metastasis and therapeutic resistance by promoting a hybrid EMT state

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Fat1 deletion promotes hybrid EMT state, tumor stemness, and metastasis

Project description:FAT1, a protocadherin, is among the most frequently mutated genes in human cancers1-5. However, the role and the molecular mechanisms by which FAT1 mutations control tumour initiation and progression are poorly understood. In the present study we used different mouse cancer models including skin squamous cell carcinoma (SCC) and lung tumours we found that Fat1 deletion accelerated tumour initiation and malignant progression and promoted hybrid epithelial to mesenchymal transition (EMT) phenotype. This hybrid EMT state was also found in FAT1 mutated human SCCs. Fat1 deleted skin SCCs presented increased tumour stemness and spontaneous metastasis. Transcriptional and chromatin profiling revealed that Yap1 and Sox2 are involved in promoting and stabilizing hybrid EMT state. To unravel the molecular mechanisms by which FAT1 (a protein located on the plasma membrane), lead to the transcriptional changes, we performed phosphor-proteomic analysis of A388 FAT1 WT human SCC cell lines and A388 FAR1 CRISPR KO. This analysis revealed that FAT1 loss of function activates a CAMK2/CD44/SRC axis that promotes YAP/ZEB1 nuclear translocation and stimulates the mesenchymal state, as well as a CAMK2-EZH2 axis that promotes activation of SOX2, which sustains the epithelial state. This comprehensive analysis also identified drug resistance and vulnerabilities in FAT1 deficient tumours with important implications for cancer therapy. Altogether, our studies revealed that Fat1 loss of function promotes tumour initiation, progression, invasiveness, stemness and metastasis through the induction of a hybrid EMT state.

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

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