Twist1 induces distinct cell states depending on TGFBR1-activation.
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.
Institute of Stem Cell Research, Helmholtz Center Munich, Neuherberg, Germany.
Diana
D
Dragoi
Institute of Stem Cell Research, Helmholtz Center Munich, Neuherberg, Germany.
Anja
A
Krattenmacher
Department of General, Visceral and Pediatric Surgery, University Medical Center, Georg-August-University Göttingen, Göttingen, Germany.
Vivek K
VK
Mishra
Institute of Stem Cell Research, Helmholtz Center Munich, Neuherberg, Germany.
Johanna M
JM
Schmidt
Institute of Stem Cell Research, Helmholtz Center Munich, Neuherberg, Germany.
Uwe J
UJ
Kloos
Institute of Stem Cell Research, Helmholtz Center Munich, Neuherberg, Germany.
Lisa K
LK
Meixner
Research Unit Protein Science, Helmholtz Center Munich, Neuherberg, Germany.
Stefanie M
SM
Hauck
Institute of Computational Biology, Helmholtz Center Munich, Neuherberg, Germany.
Felix
F
Buggenthin
Institute of Computational Biology, Helmholtz Center Munich, Neuherberg, Germany.
Dennis
D
Schwartz
Institute of Computational Biology, Helmholtz Center Munich, Neuherberg, Germany.
Carsten
C
Marr
Department of General, Visceral and Pediatric Surgery, University Medical Center, Georg-August-University Göttingen, Göttingen, Germany.
Steven A
SA
Johnsen
Institute of Stem Cell Research, Helmholtz Center Munich, Neuherberg, Germany.
Christina H
CH
Scheel
D000072283:A549 Cells; D049109:Cell Proliferation / Q000235:genetics*; D002478:Cells, Cultured; D004847:Epithelial Cells / Q000378:metabolism; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic; D057809:HEK293 Cells; D006801:Humans; D015151:Immunoblotting; D042361:Mammary Glands, Human / Q000166:cytology; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism; D034622:RNA Interference; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000235:genetics; D051879:Twist-Related Protein 1 / Q000235:genetics* / Q000378:metabolism
D018125:Receptors, Transforming Growth Factor beta; D051879:Twist-Related Protein 1; D017346:Protein Serine-Threonine Kinases; D000077293:Receptor, Transforming Growth Factor-beta Type I; C000625841:TGFBR1 protein, human
TGFBR1; Twist1; breast cancer; context dependence; epithelial-mesenchymal transition