Twist1 induces distinct cell states depending on TGFBR1-activation
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Diana Dragoi1, Anja Krattenmacher1, Vivek K. Mishra2, Johanna M. Schmidt1, Uwe J. Kloos1, Lisa K. Meixner1, Stefanie M. Hauck3, Felix Buggenthin4, Dennis Schwartz4, Carsten Marr4, Steven A. Johnsen2 and Christina H. Scheel1
1 Institute of Stem Cell Research, Helmholtz Center Munich, Neuherberg, Germany
2 Department of General, Visceral and Pediatric Surgery, University Medical Center, Georg-August-University Göttingen, Göttingen, Germany
3 Research Unit Protein Science, Helmholtz Center Munich, Neuherberg, Germany
4 Institute of Computational Biology, Helmholtz Center Munich, Neuherberg, Germany
Christina H. Scheel, email:
Keywords: Twist1, TGFBR1, epithelial-mesenchymal transition, breast cancer, context dependence
Received: April 05, 2016 Accepted: April 09, 2016 Published: April 20, 2016
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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