The transcription factor Twist1 can promote the dissemination of epithelial cells without repressing E-cadherin or converting them into mesenchymal cells, Shamir et al. reveal.
Cancer cells are generally thought to metastasize by undergoing an epithelial to mesenchymal transition (EMT), in which transcription factors such as Twist1 down-regulate the intercellular adhesion molecule E-cadherin, allowing cells to detach from the tumor and disseminate into the surrounding tissue. However, while studying normal mammary gland development, Shamir et al. discovered that breast epithelial cells don’t disseminate in the absence of E-cadherin. Mammary ducts lacking E-cadherin became disorganized and failed to undergo branching morphogenesis in vitro and in vivo, but the epithelial cells remained attached to each other and didn’t disperse into the surrounding extracellular matrix.
Shamir et al. found that expression of Twist1 was sufficient to induce dissemination of normal cells. Surprisingly, however, rapid cell migration out of the epithelium occurred without transcriptional changes in the expression of E-cadherin or other key epithelial markers. Though E-cadherin protein levels were reduced, the adhesion molecule still localized to the plasma membrane, even in single cells migrating away from the mammary epithelium. In fact, knocking out E-cadherin prevented Twist1 from inducing cell dissemination, although the mechanism for this is unclear.
Instead of inducing a transition to mesenchymal fate, Twist1 seems to activate an epithelial motility program involving changes in the expression of genes that regulate the extracellular matrix and cell–matrix adhesion. Many of these genes are also altered in a variety of cancers. Senior author Andrew Ewald now wants to study how this pathway promotes cell dissemination and plans to investigate whether any of Twist1’s downstream effectors could be therapeutically targeted to inhibit tumor metastasis.
Text by Ben Short