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

Carman Man Chung Li, Vasilena Gocheva, Madeleine J. Oudin, Arjun Bhutkar, Shi Yun Wang, Saya R. Date, Sheng Rong Ng, Charles A. Whittaker, Roderick T. Bronson, Eric L. Snyder, Frank B. Gertler, Tyler Jacks

Research output: Contribution to journalArticlepeer-review

70 Scopus citations

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 protooncogene Hmga2, and the epithelial-to-mesenchymal mediator Snail. Finally, analyses of tumors from a genetically engineered mouse model and patients showthat 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.

Original languageEnglish
Pages (from-to)1850-1862
Number of pages13
JournalGenes and Development
Volume29
Issue number17
DOIs
StatePublished - 1 Sep 2015
Externally publishedYes

Keywords

  • Cdx2
  • Foxa2
  • Genetically engineered mouse model of cancer
  • Lung adenocarcinoma
  • Metastasis
  • Nkx2-1

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