NT/TCF signaling through LEF1 and HOXB9 mediates lung adenocarcinoma metastasis

Cancer Biology and Genetics Program, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
Cell (Impact Factor: 32.24). 08/2009; 138(1):51-62. DOI: 10.1016/j.cell.2009.04.030
Source: PubMed


Metastasis from lung adenocarcinoma can occur swiftly to multiple organs within months of diagnosis. The mechanisms that confer this rapid metastatic capacity to lung tumors are unknown. Activation of the canonical WNT/TCF pathway is identified here as a determinant of metastasis to brain and bone during lung adenocarcinoma progression. Gene expression signatures denoting WNT/TCF activation are associated with relapse to multiple organs in primary lung adenocarcinoma. Metastatic subpopulations isolated from independent lymph node-derived lung adenocarcinoma cell lines harbor a hyperactive WNT/TCF pathway. Reduction of TCF activity in these cells attenuates their ability to form brain and bone metastases in mice, independently of effects on tumor growth in the lungs. The WNT/TCF target genes HOXB9 and LEF1 are identified as mediators of chemotactic invasion and colony outgrowth. Thus, a distinct WNT/TCF signaling program through LEF1 and HOXB9 enhances the competence of lung adenocarcinoma cells to colonize the bones and the brain. For a video summary of this article, see the PaperFlick file available with the online Supplemental Data.

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Available from: Xiang Zhang, Mar 04, 2014
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    • "To address this, we first established an experimental model for the analysis of lung ADC metastasis. Because lung ADC typically metastasizes to multiple organs (including bones, the adrenal glands, the brain, and the liver) (Nguyen et al. 2009), with lung ADC cells released from the primary site traveling via the arterial circulation to distant organ sites, Figure 2. DOCK4 expression is correlated with activity of TGF-b signaling and recurrence-free survival in lung ADC. (A) Representative images of IHC stainings for p-Smad3 and DOCK4 in human lung ADC TMAs. "
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    ABSTRACT: The mechanisms by which TGF-β promotes lung adenocarcinoma (ADC) metastasis are largely unknown. Here, we report that in lung ADC cells, TGF-β potently induces expression of DOCK4, but not other DOCK family members, via the Smad pathway and that DOCK4 induction mediates TGF-β's prometastatic effects by enhancing tumor cell extravasation. TGF-β-induced DOCK4 stimulates lung ADC cell protrusion, motility, and invasion without affecting epithelial-to-mesenchymal transition. These processes, which are fundamental to tumor cell extravasation, are driven by DOCK4-mediated Rac1 activation, unveiling a novel link between TGF-β and Rac1. Thus, our findings uncover the atypical Rac1 activator DOCK4 as a key component of the TGF-β/Smad pathway that promotes lung ADC cell extravasation and metastasis. © 2015 Yu et al.; Published by Cold Spring Harbor Laboratory Press.
    Full-text · Article · Feb 2015 · Genes & Development
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    • "These data reveal the impact of the HOXB9-TGFβ-ATM axis on checkpoint activation and DNA repair. HOXB9 was also reported as promoter of lung adenocarcinoma metastasis and multiorgan metastatic progression of lung cancer due to its activation of the WNT/TCF pathway [18], as well as promoter of metastasis in colon cancer and potential biomarker for bevacizumab treatment [19], [20]. On the basis of these background information, we hypothesized that to target this coordinated program orchestrated by HOXB9 may be required for effective inhibition of tumor progression, and focused on the mechanisms of HOXB9 transcription. "
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    ABSTRACT: Homeobox B9 (HOXB9), a member of the homeobox gene family, is overexpressed in breast cancer and promotes tumor progression and metastasis by stimulating epithelial-to-mesenchymal transition and angiogenesis within the tumor microenvironment. HOXB9 activates the TGFβ-ATM axis, leading to checkpoint activation and DNA repair, which engenders radioresistance in breast cancer cells. Despite detailed reports of the role of HOXB9 in breast cancer, the factors that regulate HOXB9 transcription have not been extensively examined. Here we uncover an underlying mechanism that may suggest novel targeting strategies for breast cancer treatment. To identify a transcription factor binding site (TFBS) in the HOXB9 promoter region, a dual luciferase reporter assay was conducted. Protein candidates that may directly attach to a TFBS of HOXB9 were examined by Q-PCR, electrophoretic mobility shift assay (EMSA), chromatin immunoprecipitation (ChIP), and mutation analysis. A HOXB9 promoter region from -404 to -392 was identified as TFBS, and E2F1 was a potential binding candidate in this region. The induction of HOXB9 expression by E2F1 was observed by Q-PCR in several breast cancer cell lines overexpressing E2F1. The stimulatory effect of E2F1 on HOXB9 transcription and its ability to bind the TFBS were confirmed by luciferase, EMSA and ChIP assay. Immunohistochemical analysis of 139 breast cancer tissue samples revealed a significant correlation between E2F1 and HOXB9 expression (p<0.001). Furthermore, a CDK4/6 inhibitor suppressed E2F1 expression and also reduced expression of HOXB9 and its downstream target genes. Our in vitro analysis identified the TFBS of the HOXB9 promoter region and suggested that E2F1 is a direct regulator of HOXB9 expression; these data support the strong correlation we found between E2F1 and HOXB9 in clinical breast cancer samples. These results suggest that targeting the E2F1/HOXB9 axis may be a novel strategy for the control or prevention of cancer progression and metastasis.
    Full-text · Article · Aug 2014 · PLoS ONE
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    • "Beyond colon cancer, WNT-TCF signaling has been implicated in a number of other tumor types including advanced non-small cell lung cancer (Nguyen et al, 2009; Pacheco-Pinedo et al, 2011). We have therefore used H358 human metastatic lung bronchioalveolar carcinoma cells to test for a response to Ivermectin at identical doses as for colon cancer cells. "
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    ABSTRACT: Constitutive activation of canonical WNT-TCF signaling is implicated in multiple diseases, including intestine and lung cancers, but there are no WNT-TCF antagonists in clinical use. We have performed a repositioning screen for WNT-TCF response blockers aiming to recapitulate the genetic blockade afforded by dominant-negative TCF. We report that Ivermectin inhibits the expression of WNT-TCF targets, mimicking dnTCF, and that its low concentration effects are rescued by direct activation by TCFVP16. Ivermectin inhibits the proliferation and increases apoptosis of various human cancer types. It represses the levels of C-terminal β-CATENIN phosphoforms and of CYCLIN D1 in an okadaic acid-sensitive manner, indicating its action involves protein phosphatases. In vivo, Ivermectin selectively inhibits TCF-dependent, but not TCF-independent, xenograft growth without obvious side effects. Analysis of single semi-synthetic derivatives highlights Selamectin, urging its clinical testing and the exploration of the macrocyclic lactone chemical space. Given that Ivermectin is a safe anti-parasitic agent used by > 200 million people against river blindness, our results suggest its additional use as a therapeutic WNT-TCF pathway response blocker to treat WNT-TCF-dependent diseases including multiple cancers.
    Full-text · Article · Aug 2014 · EMBO Molecular Medicine
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