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

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 long , the embryonal protooncogene 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: lung adenocarcinoma; metastasis; Nkx2-1; Foxa2; Cdx2; genetically engineered mouse model of cancer] Supplemental material is available for this article.

Stromal Expression of miR-143/145 Promotes Neoangiogenesis in Lung Cancer Development

“…Independent Component Analysis (ICA), targeted pair-wise differential expression analysis, and gene set enrichment analysis (GSEA) were performed as described in (45). All primary RNA-seq data are available at Gene Expression Omnibus (GSE71877).…”

Emerging Biological Principles of Metastasis

“…In human breast cancer cells, the activation of key stem cells pathways, such as Wnt and Notch signaling, is also important for supporting their colonization in xenograft mouse models (Oskarsson et al, 2011). And mouse models of lung adenocarcinoma have revealed that metastatic progression is associated with a dedifferentiation program, mediated by loss of Nkx2-1 expression, which resembles programs operating in stem-like states (Li et al, 2015; Winslow et al, 2011). Thus, it appears that the metastatic potential of a carcinoma is closely related to its ability to dispatch populations of CSCs that can re-initiate tumor growth following arrival at distant sites (Oskarsson et al, 2014).…”

Fox transcription factors: from development to disease

“…1) based on sequence similarity within and outside of the forkhead box (Hannenhalli and Kaestner, 2009;Kaestner et al, 1999). In many cases, the homozygous deletion of just one Fox gene leads to embryonic or perinatal lethality and, in humans, mutations in or the abnormal regulation of Fox genes are associated with developmental disorders and diseases such as cancer Li et al, 2015a;Wang et al, 2014b;Zhu et al, 2015;DeGraff et al, 2014;Halmos et al, 2004;Ren et al, 2015;Jones et al, 2015;Habashy et al, 2008), Parkinson's disease (Kittappa et al, 2007), autism spectrum disorder (Bowers and Konopka, 2012), ocular abnormalities (Acharya et al, 2011), defects in immune regulation and function (Mercer and Unutmaz, 2009) and deficiencies in language acquisition (Takahashi et al, 2009); see Table 1 for a comprehensive overview of Fox transcription factor expression patterns and their association with developmental disorders and disease.…”