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Overexpression of lung developmental transcription factors TTF-1, NKX2-8 and PAX9

ABSTRACT: We investigated the clinical implications of lung developmental transcription factors (TTF-1, NKX2-8, and PAX9) which we recently discovered as cooperating oncogenes activated by way of gene amplification at chromosome 14q13 in lung cancer. Using stable transfectants of human bronchial epithelial cells, RNA expression profiles (signatures) representing activation of the biological pathways defined by each of the three genes were determined and used to risk stratify a non-small cell lung cancer (NSCLC) clinical dataset consisting of ninety-one early stage tumors. Co-activation of the TTF-1 and NKX2-8 pathways identified a cluster of patients with poor survival, representing approximately 20% of patients with early stage NSCLC, whereas activation of individual pathways did not reveal significant prognostic power. Importantly, the poor prognosis associated with co-activation of TTF-1 and NKX2-8 was validated in two other independent clinical datasets. Further, lung cancer cell lines showing co-activation of the TTF-1 and NKX2-8 pathways were shown to exhibit resistance to cisplatin, the standard of care for the treatment of NSCLC. Since TTF-1 and NKX2-8 lack specific inhibitors at the current time, we explored an alternative therapeutic strategy. Using signatures of signaling pathway activation, we identified deregulation of specific oncogenic pathways (Ras and Myc) in the TTF-1/NKX2-8 co-activated cohort. In vitro experiments demonstrated the ability of a Ras pathway-specific therapy to inhibit tumor cell growth in TTF-1/NKX-2 activated cells, thus, suggesting that modulation of the Ras pathway is a rational strategy to targeted therapy in high risk NSCLC patients with co-activation of specific lung developmental pathways. Keywords: Transcription factor expression analysis

ORGANISM(S): Homo sapiens

PROVIDER: GSE9212 | GEO | 2009/04/01

SECONDARY ACCESSION(S): PRJNA102799

REPOSITORIES: GEO

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Project description:Despite the high prevalence and poor outcome of patients with metastatic lung cancer, the mechanisms of tumour progression and metastasis remain largely uncharacterized. We modelled human lung adenocarcinoma, which frequently harbours activating point mutations in KRAS1 and inactivation of the p53-pathway2, using conditional alleles in mice3-5. Lentiviral-mediated somatic activation of oncogenic Kras and deletion of p53 in the lung epithelial cells of KrasLSL-G12D/+;p53flox/flox mice initiates lung adenocarcinoma development4. Although tumours are initiated synchronously by defined genetic alterations, only a subset become malignant, suggesting that disease progression requires additional alterations. Identification of the lentiviral integration sites allowed us to distinguish metastatic from non-metastatic tumours and determine the gene expression alterations that distinguish these tumour types. Cross-species analysis identified the NK-2 related homeobox transcription factor Nkx2-1 (Ttf-1/Titf1) as a candidate suppressor of malignant progression. In this mouse model, Nkx2-1-negativity is pathognomonic of high-grade poorly differentiated tumours. Gain- and loss-of-function experiments in cells derived from metastatic and non-metastatic tumours demonstrated that Nkx2-1 controls tumour differentiation and limits metastatic potential in vivo. Interrogation of Nkx2-1 regulated genes, analysis of tumours at defined developmental stages, and functional complementation experiments indicate that Nkx2-1 constrains tumours in part by repressing the embryonically-restricted chromatin regulator Hmga2. While focal amplification of NKX2-1 in a fraction of human lung adenocarcinomas has focused attention on its oncogenic function6-9, our data specifically link Nkx2-1 downregulation to loss of differentiation, enhanced tumour seeding ability, and increased metastatic proclivity. Thus, the oncogenic and suppressive functions of Nkx2-1 in the same tumour type substantiate its role as a dual function lineage factor. 23 cell lines derived from primary tumor or metastasis. 6 samples analyzed to determine the effect of Nkx2-1 knockdown on gene expression

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Overexpression of lung developmental transcription factors TTF-1, NKX2-8 and PAX9

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