title: Stem-cell-like properties and epithelial plasticity arise as stable traits after transient Twist1 activation.
abstract: Master regulators of the epithelial-mesenchymal transition such as Twist1 and Snail1 have been implicated in invasiveness and the generation of cancer stem cells, but their persistent activity inhibits stem-cell-like properties and the outgrowth of disseminated cancer cells into macroscopic metastases. Here, we show that Twist1 activation primes a subset of mammary epithelial cells for stem-cell-like properties, which only emerge and stably persist following Twist1 deactivation. Consequently, when cells undergo a mesenchymal-epithelial transition (MET), they do not return to their original epithelial cell state, evidenced by acquisition of invasive growth behavior and a distinct gene expression profile. These data provide an explanation for how transient Twist1 activation may promote all steps of the metastatic cascade; i.e., invasion, dissemination, and metastatic outgrowth at distant sites.
authors.affiliation: Institute of Stem Cell Research, Helmholtz Center for Health and Environmental Research Munich, 85764 Neuherberg, Germany.
authors.forename: Johanna M
authors.initials: JM
authors.lastname: Schmidt
authors.affiliation: Institute of Stem Cell Research, Helmholtz Center for Health and Environmental Research Munich, 85764 Neuherberg, Germany.
authors.forename: Elena
authors.initials: E
authors.lastname: Panzilius
authors.affiliation: Institute of Pathology, Medical School, Ludwig Maximilian University, 80337 Munich, Germany.
authors.forename: Harald S
authors.initials: HS
authors.lastname: Bartsch
authors.affiliation: Institute of Experimental Genetics, Helmholtz Center Munich, 85764 Neuherberg, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Irmler
authors.affiliation: Institute of Experimental Genetics, Helmholtz Center Munich, 85764 Neuherberg, Germany; Department of Experimental Genetics, Technical University Munich, 85354 Freising, Germany.
authors.forename: Johannes
authors.initials: J
authors.lastname: Beckers
authors.affiliation: Department of General, Visceral and Pediatric Surgery, University Medical Center, 37075 Göttingen, Germany.
authors.forename: Vijayalakshmi
authors.initials: V
authors.lastname: Kari
authors.affiliation: Institute of Stem Cell Research, Helmholtz Center for Health and Environmental Research Munich, 85764 Neuherberg, Germany.
authors.forename: Jelena R
authors.initials: JR
authors.lastname: Linnemann
authors.affiliation: Institute of Stem Cell Research, Helmholtz Center for Health and Environmental Research Munich, 85764 Neuherberg, Germany.
authors.forename: Diana
authors.initials: D
authors.lastname: Dragoi
authors.affiliation: Institute of Stem Cell Research, Helmholtz Center for Health and Environmental Research Munich, 85764 Neuherberg, Germany.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Hirschi
authors.affiliation: Institute of Stem Cell Research, Helmholtz Center for Health and Environmental Research Munich, 85764 Neuherberg, Germany.
authors.forename: Uwe J
authors.initials: UJ
authors.lastname: Kloos
authors.affiliation: Institute of Computational Biology, Helmholtz Center Munich, 85764 Neuherberg, Germany.
authors.forename: Steffen
authors.initials: S
authors.lastname: Sass
authors.affiliation: Institute of Computational Biology, Helmholtz Center Munich, 85764 Neuherberg, Germany; Department of Mathematics, Technical University Munich, 85747 Garching, Germany.
authors.forename: Fabian
authors.initials: F
authors.lastname: Theis
authors.affiliation: Department of Obstetrics and Gynecology, Medical School, Ludwig Maximilian University, 80337 Munich, Germany.
authors.forename: Steffen
authors.initials: S
authors.lastname: Kahlert
authors.affiliation: Department of General, Visceral and Pediatric Surgery, University Medical Center, 37075 Göttingen, Germany.
authors.forename: Steven A
authors.initials: SA
authors.lastname: Johnsen
authors.affiliation: Institute of Pathology, Medical School, Ludwig Maximilian University, 80337 Munich, Germany.
authors.forename: Karl
authors.initials: K
authors.lastname: Sotlar
authors.affiliation: Institute of Stem Cell Research, Helmholtz Center for Health and Environmental Research Munich, 85764 Neuherberg, Germany. Electronic address: christina.scheel@helmholtz-muenchen.de.
authors.forename: Christina H
authors.initials: CH
authors.lastname: Scheel
mesh_terms: D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology; D018929:Cell Culture Techniques; D002460:Cell Line; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004847:Epithelial Cells / Q000166:cytology / Q000378:metabolism; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects; D005260:Female; D006801:Humans; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D000071250:Snail Family Transcription Factors; D013234:Stem Cells / Q000166:cytology / Q000378:metabolism; D013629:Tamoxifen / Q000494:pharmacology; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D051879:Twist-Related Protein 1 / Q000235:genetics / Q000378:metabolism*
chemical_list: D018931:Antineoplastic Agents, Hormonal; D009687:Nuclear Proteins; C000604407:SNAI1 protein, human; D000071250:Snail Family Transcription Factors; C103173:TWIST1 protein, human; D014157:Transcription Factors; D051879:Twist-Related Protein 1; D013629:Tamoxifen