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


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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    • "The basis for tumor cell dormancy may be the initial EMT process itself. In squamous cell carcinoma, spatiotemporal regulation of the epithelial–mesenchymal transition is essential for the dissemination and eventual metastasis (Tsai et al, 2012). The mesenchymal phenotype of CTCs that underwent EMT promotes motility but does not favor growth (Celia-Terrassa et al, 2012). "
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    ABSTRACT: Cancer metastasis is the main cause of cancer-related death, and dissemination of tumor cells through the blood circulation is an important intermediate step that also exemplifies the switch from localized to systemic disease. Early detection and characterization of circulating tumor cells (CTCs) is therefore important as a general strategy to monitor and prevent the development of overt metastatic disease. Furthermore, sequential analysis of CTCs can provide clinically relevant information on the effectiveness and progression of systemic therapies (e.g., chemo-, hormonal, or targeted therapies with antibodies or small inhibitors). Although many advances have been made regarding the detection and molecular characterization of CTCs, several challenges still exist that limit the current use of this important diagnostic approach. In this review, we discuss the biology of tumor cell dissemination, technical advances, as well as the challenges and potential clinical implications of CTC detection and characterization.
    EMBO Molecular Medicine 11/2014; 7(1). DOI:10.15252/emmm.201303698 · 8.67 Impact Factor
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    • "However, for the second phase of metastasis, reversal of EMT (i.e. MET) is required for the tumor cells in circulation to colonize and form metastatic lesions [34]. Here, we would focus on discussion of the first phase of metastasis, in particular EMT and vascular modulation . "
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    ABSTRACT: Metastasis refers to the spread of cancer cells from a primary tumor to distant organs mostly via the bloodstream. During the metastatic process, cancer cells invade blood vessels to enter circulation, and later exit the vasculature at a distant site. Endothelial cells that line blood vessels normally serve as a barrier to the movement of cells into or out of the blood. It is thus critical to understand how metastatic cancer cells overcome the endothelial barrier. Epithelial cancer cells acquire increased motility and invasiveness through epithelial-to-mesenchymal transition (EMT), which enables them to move toward vasculature. Cancer cells also express a variety of adhesion molecules that allow them to attach to vascular endothelium. Finally, cancer cells secrete or induce growth factors and cytokines to actively prompt vascular hyperpermeability that compromises endothelial barrier function and facilitates transmigration of cancer cells through the vascular wall. Elucidation of the mechanisms underlying metastatic dissemination may help develop new anti-metastasis therapeutics. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.
    Cancer Letters 10/2014; DOI:10.1016/j.canlet.2014.10.031 · 5.62 Impact Factor
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    • "For basal-like BC patients, BLBC, but not WCLS, ranked high (2 nd ) compared to 1,000 random signatures of similar composition (Supplementary Fig S4C). The better prognosis of WCLS-negative versus WCLS-positive patients suggests that overt activation of EMT/mesenchymal pathways may improve outcome by blocking mesenchymal-to-epithelial transition (MET), which is required for metastatic growth at distal sites (Ocana et al, 2012; Tsai et al, 2012). In this case, an EMT signature should also not be associated with worse outcome. "
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    ABSTRACT: The tumor suppressors Pten and p53 are frequently lost in breast cancer, yet the consequences of their combined inactivation are poorly understood. Here, we show that mammary-specific deletion of Pten via WAP-Cre, which targets alveolar progenitors, induced tumors with shortened latency compared to those induced by MMTV-Cre, which targets basal/luminal progenitors. Combined Pten-p53 mutations accelerated formation of claudin-low, triple-negative-like breast cancer (TNBC) that exhibited hyper-activated AKT signaling and more mesenchymal features relative to Pten or p53 single-mutant tumors. Twenty-four genes that were significantly and differentially expressed between WAP-Cre:Pten/p53 and MMTV-Cre:Pten/p53 tumors predicted poor survival for claudin-low patients. Kinome screens identified eukaryotic elongation factor-2 kinase (eEF2K) inhibitors as more potent than PI3K/AKT/mTOR inhibitors on both mouse and human Pten/p53-deficient TNBC cells. Sensitivity to eEF2K inhibition correlated with AKT pathway activity. eEF2K monotherapy suppressed growth of Pten/p53-deficient TNBC xenografts in vivo and cooperated with doxorubicin to efficiently kill tumor cells in vitro. Our results identify a prognostic signature for claudin-low patients and provide a rationale for using eEF2K inhibitors for treatment of TNBC with elevated AKT signaling.
    EMBO Molecular Medicine 10/2014; 6(12):1542-1560. DOI:10.15252/emmm.201404402 · 8.67 Impact Factor
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