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Cancer Cell Article Spatiotemporal Regulation of Epithelial-Mesenchymal Transition Is Essential for Squamous Cell Carcinoma Metastasis Jeff H.

Tsai,1 Joana Liu Donaher,3 Danielle A. Murphy,4 Sandra Chau,1 and Jing Yang1,2,* 1Department of Pharmacology 2Department of Pediatrics University of California, San Diego, School of Medicine,

9500 Gilman Drive, La Jolla, CA 92093-0636, USA 3Whitehead Institute for Biomedical Research,

9 Cambridge Center, Cambridge, MA 02142, USA 4The Sanford Burnham Medical Research Institute, La Jolla, CA 92037, USA *Correspondence: jingyang@ucsd.edu http://dx.doi.org/10.1016/j.ccr.2012.09.022 SUMMARY Epithelial-mesenchymal transition (EMT) is implicated in converting stationary epithelial tumor cells into motile mesenchymal cells during metastasis. However, the involvement of EMT in metastasis is still contro- versial, due to the lack of a mesenchymal phenotype in human carcinoma metastases. Using a spontaneous squamous cell carcinoma mouse model, we show that activation of the EMT-inducing transcription factor Twist1 is suf?cient to promote carcinoma cells to undergo EMT and disseminate into blood circulation. Importantly, in distant sites, turning off Twist1 to allow reversion of EMT is essential for disseminated tumor cells to proliferate and form metastases. Our study demonstrates in vivo the requirement of '

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reversible EMT'

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in tumor metastasis and may resolve the controversy on the importance of EMT in carcinoma metastasis. INTRODUCTION During metastasis, epithelial tumor cells invade surrounding extracellular matrix (ECM), disseminate into the systemic circula- tion, and then establish secondary tumors in distant sites. A developmental program termed epithelial-mesenchymal transi- tion (EMT) has been implicated in giving rise to the dissemination of single carcinoma cells. During EMT, stationary epithelial cells lose their epithelial characteristics, including adherent junctions and apical-basal polarity, and acquire a mesenchymal mor- phology and the ability to migrate and invade (Hay, 1995). Biochemically, cells switch off the expression of epithelial markers, such as adherens junction proteins E-cadherin and catenins, and turn on mesenchymal markers, including vimentin and ?bronectin. Studies using cell culture and tumor xenograft models show that activation of EMT promotes carcinoma cells to dissociate from each other and metastasize to distant organs (Hay, 1995;

Kalluri and Weinberg, 2009;

Thiery, 2002, 2009). However, the involvement of EMT in tumor metastasis in vivo is still hotly debated (Garber, 2008;

Ledford, 2011;

Tarin et al., 2005;

Thompson et al., 2005). In human carcinoma, although primary tumors show many morphological and molecular features of EMT in subpopulations of invasive cells, distant metastases present an epithelial morphology (Peinado et al., 2007). This phenomenon contradicts the assumption that activa- tion of EMT in tumor cells should result in metastases with a mesenchymal phenotype, therefore casting doubts on the occurrence of EMT during metastasis. This discrepancy could be due to the interpretation of the EMT program as a permanent nonreversible course during tumor metastasis. A reversible EMT model has been proposed to explain this apparent paradox: carcinoma cells undergo EMT to invade and disseminate from the primary tumor;

once reaching distant sites, tumor cells need to revert to an epithelial identity to form macrometastases (Thiery, 2002). However, this hypothesis has not been attested in vivo. Signi?cance EMT features are frequently observed in many types of primary human carcinoma, but not their corresponding metastases. Our ?ndings 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 metastases. Cancer Cell 22, 725C736, December 11,