Foxa2 and Cdx2 cooperate with Nkx2-1 to inhibit lung adenocarcinoma metastasis.
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.
David H. Koch Institute for Integrative Cancer Research, Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA;
Carman Man-Chung
CM
Li
David H. Koch Institute for Integrative Cancer Research, Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA;
Vasilena
V
Gocheva
David H. Koch Institute for Integrative Cancer Research, Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA;
Madeleine J
MJ
Oudin
David H. Koch Institute for Integrative Cancer Research, Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA;
Arjun
A
Bhutkar
David H. Koch Institute for Integrative Cancer Research, Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA;
Shi Yun
SY
Wang
David H. Koch Institute for Integrative Cancer Research, Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA;
Saya R
SR
Date
David H. Koch Institute for Integrative Cancer Research, Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA;
Sheng Rong
SR
Ng
David H. Koch Institute for Integrative Cancer Research, Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA;
Charles A
CA
Whittaker
Department of Pathology, Tufts University School of Medicine and Veterinary Medicine, North Grafton, Massachusetts 01536, USA;
Roderick T
RT
Bronson
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;
Eric L
EL
Snyder
David H. Koch Institute for Integrative Cancer Research, Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA;
Frank B
FB
Gertler
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.
Tyler
T
Jacks
D000230:Adenocarcinoma / Q000235:genetics / Q000401:mortality / Q000503:physiopathology*; D000077192:Adenocarcinoma of Lung; D000818:Animals; D030801:Animals, Genetically Modified; D000071616:CDX2 Transcription Factor; D045744:Cell Line, Tumor; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D055785:Gene Knockdown Techniques; D020868:Gene Silencing; D051542:Hepatocyte Nuclear Factor 3-beta / Q000235:genetics / Q000378:metabolism*; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics / Q000401:mortality / Q000503:physiopathology*; D051379:Mice; D008819:Mice, Nude; D009362:Neoplasm Metastasis / Q000235:genetics*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D000090063:Proto-Oncogene Mas; D000074482:Thyroid Nuclear Factor 1; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
D000071616:CDX2 Transcription Factor; C491270:CDX2 protein, human; C496502:FOXA2 protein, human; D018398:Homeodomain Proteins; C000715470:MAS1 protein, human; C000614414:Nkx2-1 protein, mouse; D009687:Nuclear Proteins; D000090063:Proto-Oncogene Mas; D000074482:Thyroid Nuclear Factor 1; D014157:Transcription Factors; D051542:Hepatocyte Nuclear Factor 3-beta
Cdx2; Foxa2; Nkx2-1; genetically engineered mouse model of cancer; lung adenocarcinoma; metastasis