Twist1-induced dissemination preserves epithelial identity and requires E-cadherin

Eliah R. Shamir, Elisa Pappalardo, Danielle M. Jorgens, Kester Coutinho, Wen Ting Tsai, Khaled Aziz, Manfred Auer, Phuoc T. Tran, Joel S. Bader, Andrew J. Ewald

Research output: Contribution to journalArticle

108 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)839-856
Number of pages18
JournalJournal of Cell Biology
Volume204
Issue number5
DOIs
StatePublished - Mar 2014

ASJC Scopus subject areas

  • Cell Biology

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    Shamir, E. R., Pappalardo, E., Jorgens, D. M., Coutinho, K., Tsai, W. T., Aziz, K., Auer, M., Tran, P. T., Bader, J. S., & Ewald, A. J. (2014). Twist1-induced dissemination preserves epithelial identity and requires E-cadherin. Journal of Cell Biology, 204(5), 839-856. https://doi.org/10.1083/jcb.201306088