Editors' ChoiceCancer

Sox2 Holds the Key to Lung Cancer Susceptibility

Science Signaling  09 Sep 2014:
Vol. 7, Issue 342, pp. ec243
DOI: 10.1126/scisignal.2005877

Some cells respond to oncogenic mutations by becoming cancerous and others do not. For example, in mice, when all cells of the lung contain a cancer-causing mutant of the protein K-RAS, K-RASG12D, which is a common mutation associated with non–small cell lung cancer in humans, only a subset of alveolar cells form adenocarcinomas. Notch signaling is an important pathway in lung development and contributes to some forms of lung cancer. Xu et al. identified a mechanism by which different cells in the lung exhibit different responses to the mutant K-RAS depending on the amount of Notch signaling. The authors generated mice engineered to express K-RASG12D in a subset of alveolar type II cells with or without the coexpression of an inhibitor of Notch-dependent transcriptional regulation (DNMaml1). Lungs of DNMaml1, K-RASG12D mice had hyperplastic lesions and small adenomas, whereas lungs of K-RASG12D mice had many large adenocarcinomas and adenomas, indicating that Notch signaling promotes or is permissive for oncogenesis in these cells. Whereas the tumors in the lungs of K-RASG12D mice were not positive for the transcription factor Sox2, the hyperplastic lesions in the lungs of DNMaml1, K-RASG12D mice were positive for Sox2 and two markers of epithelial cells (Trp63 and Krt5), suggesting that by enabling Sox2 expression DNMam1l may drive the cells toward a squamous or epithelial cell hyperplastic phenotype that does not progress to cancer. Consistent with a cancer-promoting effect of Notch signaling, coexpression of K-RASG12D and the Notch intracellular domain (NICD, the transcriptionally active fragment of Notch) caused the development of adenocarcinomas in the airways and alveoli of the mice. Sox2 is present in the epithelial cells of the airway and not in the distal alveoli, and the airway adenocarcinomas induced by K-RASG12D and NICD were positive for Sox2. Microarray and chromatin immunoprecipitation analysis indicated that Sox2 bound and inhibited the expression of Notch1 and Notch2 and the Notch target gene Hes1. In K-RASG12D mice, inducible loss of Sox2 resulted in tumorigenesis in the airways, whereas overexpression of Sox2 inhibited the progression from hyperplasia and adenoma to adenocarcinoma in the alveoli. Thus, the susceptibility of the different cells of the lung to transformation and tumor progression is related to the presence of tumor-limiting effects of Sox2, which inhibits the expression of the tumor-permissive Notch-encoding genes in the airway but not in the alveoli.

X. Xu, L. Huang, C. Futtner, B. Schwab, R. R. Rampersad, Y. Lu, T. A. Sporn, B. L. M. Hogan, M. W. Onaitis, The cell of origin and subtype of K-Ras-induced lung tumors are modified by Notch and Sox2. Genes Dev. 28, 1929–1939 (2014). [Abstract] [Full Text]