Lineage-Specific Dependency of Lung Adenocarcinomas on the Lung Development Regulator TTF-1

Abstract

Emerging evidence, although currently very sparse, suggests the presence of ''lineage-specific dependency'' in the survival mechanisms of certain cancers. TTF-1 has a decisive role as a master regulatory transcription factor in lung development and in the maintenance of the functions of terminal respiratory unit (TRU) cells. We show that a subset of lung adenocarcinoma cell lines expressing TTF-1, which presumably represent those derived from the TRU lineage, exhibit marked dependence on the persistent expression of TTF-1. The inhibition of TTF-1 by RNA interference (RNAi) significantly and specifically induced growth inhibition and apoptosis in these adenocarcinoma cell lines. Furthermore, a fraction of TTF-1-expressing tumors and cell lines displayed an increase in the gene dosage of TTF-1 in the analysis of 214 patients with non-small-cell lung cancer, including 174 adenocarcinomas, showing a tendency of higher frequency of increased gene copies at metastatic sites than at primary sites (P = 0.07, by two-sided Fisher's exact test). These findings strongly suggest that in addition to the development and maintenance of TRU lineages in normal lung, sustained TTF-1 expression may be crucial for the survival of a subset of adenocarcinomas that express TTF-1, providing credence for the lineage-specific dependency model. [Cancer Res 2007; 67(13):6007-11]

Characterizing the developmental pathways TTF-1 , NKX2–8 , and PAX9 in lung cancer

“…Whereas overexpression of individual members of this 3-gene set in the core region of the amplicon was ineffective in stimulating proliferation, combinatorial overexpression of the genes led to significant proliferation of premalignant human bronchial epithelial cells, implicating oncogene cooperation for the 3 coamplified lung development regulators. Furthermore, our reported RNAi knockdown experiments in concert with other reports establish that each of these 3 genes can have essential tumor maintenance function (5,8,9).…”

“…All 3 genes are localized to a unique, recurrent lung cancer amplicon at 14q13.3. Given its essential function in lung development and relative restrictive expression in lung tissue, TTF-1 is an appealing candidate as a cell lineage-survival oncogene in lung cancer, similar to the MITF oncogene specific to melanoma (2,8). However, our recent discovery of TTF-1, NKX2-8, and PAX9 as coamplified oncogenes with functional synergism suggests that the 14q13.3 amplicon in lung cancer provides selective advantage to tumor cells by way of activation of multiple oncogenes, not just TTF-1 (5).…”

Oncogenic cooperation and coamplification of developmental transcription factor genes in lung cancer

“…Interestingly, given its essential function in lung development (34,35) and restrictive expression in lung tissue (36), TTF1 was speculated to be an appealing candidate cell lineage-survival oncogene in lung cancer (32). Very recently, Tanaka et al (37) provided evidence that sustained TTF1 expression may be crucial for a subset of lung AC. However, in light of the findings of our study, we believe there are several lines of evidence suggesting that TTF1 as well as NKX28 and PAX9 are lung cell lineage addiction oncogenes.…”

Progenitor stem cell marker expression by pulmonary carcinomas

“…15,28 By contrast, adenocarcinomas, more commonly a peripheral tumor, are felt to arise from progenitor cells in the terminal respiratory unit (TRU). 29 There is no evidence of a precursor cell for small cell carcinoma. Our results, however, suggest a great overlap of progenitor/stem cell markers among the different histological types of lung carcinomas.…”