Abstract B48: Spatiotemporal regulation of epithelial-mesenchymal transition is essential for carcinoma metastasis

During metastasis, epithelial tumor cells dissociate from each other, invade surrounding extracellular matrix, disseminate into the systemic circulation, and then establish secondary lesions in distant sites. A developmental program termed Epithelial-Mesenchymal Transition (EMT) has been implicated in giving rise to the dissemination of single carcinoma cells. During EMT, stationary epithelial cells undergo a series of cellular and molecular changes to convert into motile mesenchymal cells. However, the involvement of EMT in tumor metastasis is still controversial primarily due to the lack of a mesenchymal phenotype in human carcinoma distant metastases. In this study, we established a transgenic mouse model that specifically expresses the EMT-inducing transcription factor Twist1 on the basal layer of the skin in an inducible fashion. Using a chemical carcinogenesis skin tumor model, we report here that induction of Twist1 is sufficient to promote carcinoma cells to undergo EMT, invade through basement membrane, intravasate into blood circulation, and extravasate into distant organs. More importantly, we found that in distant sites, turning off Twist1 to allow reversion of EMT is essential for tumor cells to proliferate and form epithelial macrometastases. In contrast, continuous expression of Twist1 in disseminated tumor cells inhibits metastasis formation in distant organs. Consistent with these results, we found that expression of Twist1 is significantly higher in primary human carcinomas compared to their corresponding distant metastases. These results indicate that carcinoma cells undergo EMT to disseminate; once reaching distant site, they need to revert to an epithelial identity to form macrometastases. Our study demonstrates in vivo the requirement of “reversible EMT” in tumor metastasis and may resolve the controversy on the importance of EMT in carcinoma metastasis. EMT features are frequently observed in many types of primary human carcinoma, but not their corresponding metastases. Our findings indicate that reversible EMT likely represents a key driving force in human carcinoma metastasis. Delayed onset of metastasis following primary tumor removal is thought to be due to resurrection of latent carcinoma cells in distant organs. Our study raises the possibility that tumor dormancy could be due to the inability of disseminated tumor cells to revert EMT and proliferate. The dynamic involvement of EMT in metastasis cautions that therapies inhibiting EMT could be counterproductive in preventing distant metastases when patients already present circulating tumor cells. Instead, blocking EMT reversion may prevent dormant tumor cells from establishing macrometastases. Citation Format: Jeff H. Tsai, Joana Liu Donaher, Danielle A. Murphy, Sandra Chau, Jing Yang. Spatiotemporal regulation of epithelial-mesenchymal transition is essential for carcinoma metastasis. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Invasion and Metastasis; Jan 20-23, 2013; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2013;73(3 Suppl):Abstract nr B48.