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Twist1 induces distinct cell states depending on TGFBR1-activation.

Oncotarget 7, 30396-30407 (2016)
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Basic helix-loop-helix transcription factor Twist1 is a master regulator of Epithelial-Mesenchymal Transition (EMT), a cellular program implicated in different stages of development as well as metastatic dissemination of carcinomas. Here, we show that Twist1 requires TGF-beta type-I receptor (TGFBR1)-activation to bind an enhancer region of downstream effector ZEB1, thereby inducing ZEB1 transcription and EMT. When TGFBR1-phosphorylation is inhibited, Twist1 generates a distinct cell state characterized by collective invasion, simultaneous proliferation and expression of endothelial markers. By contrast, TGFBR1-activation directs Twist1 to induce stable mesenchymal transdifferentiation through EMT, thereby generating cells that display single-cell invasion, but lose their proliferative capacity. In conclusion, preventing Twist1-induced EMT by inhibiting TGFβ-signaling does not generally block acquisition of invasion, but switches mode from single-cell/non-proliferative to collective/proliferative. Together, these data reveal that transient Twist1-activation induces distinct cell states depending on signaling context and caution against the use of TGFβ-inhibitors as a therapeutic strategy to target invasiveness.
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Publication type Article: Journal article
Document type Scientific Article
Keywords Tgfbr1 ; Twist1 ; Breast Cancer ; Context Dependence ; Epithelial-mesenchymal Transition; Epithelial-mesenchymal Transition; Growth-factor-beta; Human Breast-cancer; Transcription Factors; Tumor Initiation; E-cadherin; Tgf-beta; Metastasis; Family; Expression
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