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

By D. Nguyen, A. Chiang, X. Zhang, Juliet Y. Kim, M. Kris, Marc Ladanyi, W. Gerald, J. Massagué. Cell, 2009

610 citations recorded by the source corpus.

Summary 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.

Subfields: Molecular Biology

View Paper: https://www.semanticscholar.org/paper/1de32a29a861347f2e0a7583566250a5648740ed

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In Molecular Biology

1. Hans Clevers
2. R. Nusse
3. Paul Polakis
4. M. Resh
5. Elaine Fuchs
6. W. Birchmeier
7. Xi He
8. C. Blanpain

Citations in the corpus

• Wnt signaling in cancer. (2012, background): “Work from the Massague laboratory encourages us to target Wnt signaling in lung cancer, which again typically lacks pathway mutations (Nguyen et al. 2009).”
• Wnt/β-catenin signaling and disease. (2012, positive): “Evidence is being unearthed that Wnt signals contribute in a paracrine mode to the growth of cancer cells or cancer stem cells (Malanchi and Huelsken, 2009), and becausemetastasizing tumor cells bear the hallmarks of Wnt signaling (Nguyen et al., 2009), targeting Porc could be clinically important.”
• Wnt/ b -Catenin Signaling, Disease, and Emerging Therapeutic Modalities (2017, background): “On the other hand, there is substantial evidence that the outgrowth of metastatic lesions and cancer stem cells is promoted by Wnts themselves (Malladi et al., 2016; Nguyen et al., 2009; Yu et al., 2013; Tammela et al., 2017), suggesting that Porcupine targeting drugs could be beneficial.”