Article

Spatiotemporal Regulation of Epithelial-Mesenchymal Transition Is Essential for Squamous Cell Carcinoma Metastasis

Department of Pharmacology, University of California, San Diego, School of Medicine, 9500 Gilman Drive, La Jolla, CA 92093-0636, USA.
Cancer cell (Impact Factor: 23.52). 11/2012; 22(6). DOI: 10.1016/j.ccr.2012.09.022
Source: PubMed

ABSTRACT

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 controversial, 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 sufficient 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 "reversible EMT" in tumor metastasis and may resolve the controversy on the importance of EMT in carcinoma metastasis.

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    • "These cells express the mesenchymal markers vimentin, fibronectin, N-cadherin, twist, and snail, among others (Thiery et al. 2009). Similar to embryonic development, where EMT is plastic, a subset of tumor cells can revert to an epithelial phenotype (a mesenchymal–epithelial transition [MET]), which is theorized to be required for seeding of distant organs and initiation of metastatic growth (Brabletz 2012; Ocaña et al. 2012; Tsai et al. 2012). However, the molecular mechanisms by which EMT and MET occur during cancer progression are still unclear. "
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    ABSTRACT: The two major isoforms of the paired-related homeodomain transcription factor 1 (Prrx1), Prrx1a and Prrx1b, are involved in pancreatic development, pancreatitis, and carcinogenesis, although the biological role that these isoforms serve in the systemic dissemination of pancreatic ductal adenocarcinoma (PDAC) has not been investigated. An epithelial-mesenchymal transition (EMT) is believed to be important for primary tumor progression and dissemination, whereas a mesenchymal-epithelial transition (MET) appears crucial for metastatic colonization. Here, we describe novel roles for both isoforms in the metastatic cascade using complementary in vitro and in vivo models. Prrx1b promotes invasion, tumor dedifferentiation, and EMT. In contrast, Prrx1a stimulates metastatic outgrowth in the liver, tumor differentiation, and MET. We further demonstrate that the switch from Prrx1b to Prrx1a governs EMT plasticity in both mouse models of PDAC and human PDAC. Last, we identify hepatocyte growth factor ( HGF) as a novel transcriptional target of Prrx1b. Targeted therapy of HGF in combination with gemcitabine in a preclinical model of PDAC reduces primary tumor volume and eliminates metastatic disease. Overall, we provide new insights into the isoform-specific roles of Prrx1a and Prrx1b in primary PDAC formation, dissemination, and metastatic colonization, allowing for novel therapeutic strategies targeting EMT plasticity.
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    • "We find that differing phenotypic plasticity is a key determinant of differences in therapeutic resistance between CSC subpopulations . Given the importance of phenotypic plasticity in tumour invasion and metastasis (Brabletz, 2012; Tsai et al., 2012), a subpopulation of CSCs that exhibit both phenotypic plasticity and therapeutic resistance presents a potent threat and is likely to be an important target for therapeutic intervention. Our development of a method for enrichment of this most resistant CSC sub-population through cotreatment with TGFβ and RA provides a means for producing large numbers of these cells for drug development studies. "
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    ABSTRACT: Cancer stem cells (CSCs) drive tumour spread and therapeutic resistance, and can undergo epithelial-to-mesenchymal transition (EMT) and mesenchymal-to-epithelial transition (MET) to switch between epithelial and post-EMT sub-populations. Examining oral squamous cell carcinoma (OSCC), we now show that increased phenotypic plasticity, the ability to undergo EMT/MET, underlies increased CSC therapeutic resistance within both the epithelial and post-EMT sub-populations. The post-EMT CSCs that possess plasticity exhibit particularly enhanced therapeutic resistance and are defined by a CD44highEpCAMlow/−CD24+ cell surface marker profile. Treatment with TGFβ and retinoic acid (RA) enabled enrichment of this sub-population for therapeutic testing, through which the endoplasmic reticulum (ER) stressor and autophagy inhibitor Thapsigargin was shown to selectively target these cells. Demonstration of the link between phenotypic plasticity and therapeutic resistance, and development of an in vitro method for enrichment of a highly resistant CSC sub-population, provides an opportunity for the development of improved chemotherapeutic agents that can eliminate CSCs.
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    • "As the EMT features of CTCs can evolve in a spectrum of different phenotypic phases during disease progression or treatment, current efforts to characterise simultaneusly CTCs with epithelial and mesenchymal features might be the key not only to improve CTCs capture efficiency but also to increase prognostic and predictive information[7]. At the metastatic site, a reversion to an epithelial morphology, also known as mesenchymal-toepithelial transition (MET), has been postulated and proposed to be essential for disseminated tumor cells to re-enter a proliferative state and give rise to macrometastatic nodules[10]. The mechanisms underlying this process are still poorly understood. "
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