Twist1 induces distinct cell states depending on TGFBR1-activation

// Diana Dragoi 1 , Anja Krattenmacher 1 , Vivek K. Mishra 2 , Johanna M. Schmidt 1 , Uwe J. Kloos 1 , Lisa K. Meixner 1 , Stefanie M. Hauck 3 , Felix Buggenthin 4 , Dennis Schwartz 4 , Carsten Marr 4 , Steven A. Johnsen 2 and Christina H. Scheel 1 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 Gottingen, Gottingen, Germany 3 Research Unit Protein Science, Helmholtz Center Munich, Neuherberg, Germany 4 Institute of Computational Biology, Helmholtz Center Munich, Neuherberg, Germany Correspondence to: 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 Abstract 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.