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Genes Dev. 2015 Sep 1;29(17):1850-62. doi: 10.1101/gad.267393.115.

Foxa2 and Cdx2 cooperate with Nkx2-1 to inhibit lung adenocarcinoma metastasis.

Author information

1
David H. Koch Institute for Integrative Cancer Research, Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA;
2
Department of Pathology, Tufts University School of Medicine and Veterinary Medicine, North Grafton, Massachusetts 01536, USA;
3
Department of Pathology, School of Medicine, University of California at San Francisco, San Francisco, California 94143, USA; Department of Anatomy, School of Medicine, University of California at San Francisco, San Francisco, California 94143, USA;
4
David H. Koch Institute for Integrative Cancer Research, Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA; Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.

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 Tks5long, 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.

KEYWORDS:

Cdx2; Foxa2; Nkx2-1; genetically engineered mouse model of cancer; lung adenocarcinoma; metastasis

PMID:
26341558
PMCID:
PMC4573857
DOI:
10.1101/gad.267393.115
[Indexed for MEDLINE]
Free PMC Article

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