title: Twist1-induced dissemination preserves epithelial identity and requires E-cadherin.
abstract: Dissemination of epithelial cells is a critical step in metastatic spread. Molecular models of dissemination focus on loss of E-cadherin or repression of cell adhesion through an epithelial to mesenchymal transition (EMT). We sought to define the minimum molecular events necessary to induce dissemination of cells out of primary murine mammary epithelium. Deletion of E-cadherin disrupted epithelial architecture and morphogenesis but only rarely resulted in dissemination. In contrast, expression of the EMT transcription factor Twist1 induced rapid dissemination of cytokeratin-positive epithelial cells. Twist1 induced dramatic transcriptional changes in extracellular compartment and cell-matrix adhesion genes but not in cell-cell adhesion genes. Surprisingly, we observed disseminating cells with membrane-localized E-cadherin and β-catenin, and E-cadherin knockdown strongly inhibited Twist1-induced single cell dissemination. Dissemination can therefore occur with retention of epithelial cell identity. The spread of cancer cells during metastasis could similarly involve activation of an epithelial motility program without requiring a transition from epithelial to mesenchymal character.
authors.affiliation: Department of Cell Biology and 2 Department of Oncology, Center for Cell Dynamics, Johns Hopkins University School of Medicine, Baltimore, MD 21205.
authors.forename: Eliah R
authors.initials: ER
authors.lastname: Shamir
authors.forename: Elisa
authors.initials: E
authors.lastname: Pappalardo
authors.forename: Danielle M
authors.initials: DM
authors.lastname: Jorgens
authors.forename: Kester
authors.initials: K
authors.lastname: Coutinho
authors.forename: Wen-Ting
authors.initials: WT
authors.lastname: Tsai
authors.forename: Khaled
authors.initials: K
authors.lastname: Aziz
authors.forename: Manfred
authors.initials: M
authors.lastname: Auer
authors.forename: Phuoc T
authors.initials: PT
authors.lastname: Tran
authors.forename: Joel S
authors.initials: JS
authors.lastname: Bader
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Ewald
mesh_terms: D000818:Animals; D015820:Cadherins / Q000502:physiology*; D002448:Cell Adhesion; D018929:Cell Culture Techniques; D002465:Cell Movement; D021982:Cell-Matrix Junctions / Q000378:metabolism; D004847:Epithelial Cells / Q000166:cytology / Q000378:metabolism* / Q000648:ultrastructure; D004848:Epithelium / Q000378:metabolism*; D017353:Gene Deletion; D055785:Gene Knockdown Techniques; D007365:Intercellular Junctions / Q000502:physiology / Q000648:ultrastructure; D051379:Mice; D009362:Neoplasm Metastasis / Q000473:pathology; D009687:Nuclear Proteins / Q000378:metabolism / Q000502:physiology*; D014158:Transcription, Genetic; D051879:Twist-Related Protein 1 / Q000378:metabolism / Q000502:physiology*
chemical_list: D015820:Cadherins; D009687:Nuclear Proteins; D051879:Twist-Related Protein 1; C067250:Twist1 protein, mouse