Abstract
Reversion of EMT is necessary for proliferation and colonization of disseminated tumor cells.
Major finding: Reversion of EMT is necessary for proliferation and colonization of disseminated tumor cells.
Approach: TWIST1 was induced systemically or locally in a mouse model of skin carcinogenesis.
Impact: Inhibition of EMT reversion may prevent the metastatic outgrowth of dormant tumor cells.
Epithelial–mesenchymal transition (EMT) promotes the invasion and dissemination of tumor cells and enhances metastasis in xenograft models. However, in human carcinoma, distant metastases often exhibit an epithelial phenotype, casting doubt on the contribution of EMT to metastasis in vivo. To address this controversy, Tsai and colleagues used a mouse model of chemically-induced skin carcinogenesis in which TWIST1, an EMT-inducing transcription factor that is associated with increased metastasis and poor survival, was conditionally activated in skin cells by either systemic or topical administration of doxycycline to model irreversible or reversible EMT, respectively. TWIST1 expression in both models facilitated progression of benign papillomas to invasive squamous cell carcinomas with a mesenchymal morphology. Intriguingly, only restricted induction of TWIST1 at the primary tumor site, but not continuous TWIST1 induction in disseminated tumor cells, resulted in increased incidence of distant metastases. These metastases lacked TWIST1 but expressed E-cadherin, indicative of an epithelial morphology and supporting the idea that reversible EMT promotes metastasis. TWIST1-mediated EMT was necessary for intravasation of circulating tumor cells, which expressed TWIST1 and other EMT markers, into the circulation and extravasation of tumor cells out of the lung vasculature, suggesting that reversion of EMT may drive metastatic colonization. Indeed, carcinoma cell proliferation was inversely correlated with TWIST1 expression, and turning off TWIST1 induction increased the proliferation of early metastatic colonies and augmented the establishment of lung nodules compared with tumor cells that maintained TWIST1 expression. In addition, in a panel of human breast carcinoma samples, among the primary tumors with high TWIST1 expression, most of the patient-matched lymph node metastases showed reduced TWIST1 levels. These findings demonstrate that EMT plays a dynamic role in tumor metastasis and suggest that blocking EMT reversion in disseminated dormant tumor cells may prevent metastasis development.
Note: Research Watch is written by Cancer Discovery Science Writers. Readers are encouraged to consult the original articles for full details. For more Research Watch, visit Cancer Discovery online at http://CDnews.aacrjournals.org.
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