Foxa2 and Cdx2 cooperate with Nkx2-1 to inhibit lung adenocarcinoma metastasis
Name
Li-2015-Foxa2 and Cdx2 coope.pdf
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1.7 MB
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Author(s)
Li, Carman Man-Chung
Gocheva, Vasilena
Wang, Shi Yun
Date, Saya R.
Ng, Sheng Rong
Whittaker, Charles A.
Bronson, Roderick T.
Snyder, Eric L.
Oudin, Madeleine Julie
Gertler, Frank
Date Issued
September 2015
Journal
Genes & Development
Publisher
Cold Spring Harbor Laboratory Press
Citation
Li, Carman Man-Chung, Vasilena Gocheva, Madeleine J. Oudin, Arjun Bhutkar, Shi Yun Wang, Saya R. Date, Sheng Rong Ng, et al. “Foxa2 and Cdx2 Cooperate with Nkx2-1 to Inhibit Lung Adenocarcinoma Metastasis.” Genes Dev. 29, no. 17 (September 1, 2015): 1850–1862.
Version
Final published version
Abstract
Despite the fact that the majority of lung cancer deaths are due to metastasis, the molecular mechanisms driving metastatic progression are poorly understood. Here, we present evidence that loss of Foxa2 and Cdx2 synergizes with loss of Nkx2-1 to fully activate the metastatic program. These three lineage-specific transcription factors are consistently down-regulated in metastatic cells compared with nonmetastatic cells. Knockdown of these three factors acts synergistically and is sufficient to promote the metastatic potential of nonmetastatic cells to that of naturally arising metastatic cells in vivo. Furthermore, silencing of these three transcription factors is sufficient to account for a significant fraction of the gene expression differences between the nonmetastatic and metastatic states in lung adenocarcinoma, including up-regulated expression of the invadopodia component Tks5[subscript long], the embryonal proto-oncogene Hmga2, and the epithelial-to-mesenchymal mediator Snail. Finally, analyses of tumors from a genetically engineered mouse model and patients show that low expression of Nkx2-1, Foxa2, and Cdx2 strongly correlates with more advanced tumors and worse survival. Our findings reveal that a large part of the complex transcriptional network in metastasis can be controlled by a small number of regulatory nodes that function redundantly, and loss of multiple nodes is required to fully activate the metastatic program.
MIT Department
Massachusetts Institute of Technology. Department of Biology
Massachusetts Institute of Technology. Department of Mechanical Engineering
Koch Institute for Integrative Cancer Research at MIT
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DOI of Published Version
https://doi.org/10.1101/gad.267393.115
