Twist1 induces dissemination by activating an epithelial motility program that requires E‐cadherin (479.2)

Abstract

Cancer metastasis begins with dissemination of cells from an epithelial tumor. Each tumor contains many mutations and a heterogeneous cell population. As such, it has been difficult to isolate the molecular requirements for a single epithelial cell to disseminate. One posited mechanism for dissemination is activation of an epithelial to mesenchymal transition (EMT), in which repression of the cell adhesion gene E‐cadherin is considered the driving molecular event. We sought to test the sufficiency of single gene perturbations to induce dissemination in primary murine mammary epithelium. Deletion of E‐cadherin disrupted simple architecture and branching morphogenesis but rarely resulted in dissemination. In contrast, expression of the EMT transcription factor Twist1 induced rapid dissemination of cells into the extracellular matrix. Twist1 induced acute transcriptional changes in cell‐matrix adhesion genes but not in epithelial‐specific genes, including E‐cadherin. Surprisingly, knockdown of E‐cadherin inhibited Twist1‐induced single cell dissemination and promoted collective epithelial migration. We conclude that Twist1 activates an epithelial motility program without requiring a transition to mesenchymal cell fate. To date, it remains unclear why some Twist1+ cells disseminate while many remain in the epithelium. We next seek to test the sufficiency of Twist1 to induce dissemination in distinct mammary epithelial subpopulations. We anticipate that cell type‐specific differences may suggest which cells within a heterogeneous tumor have the highest metastatic potential.