The cell of origin and subtype of K-Ras-induced lung tumors are modified by Notch and Sox2.
Genes Dev
; 28(17): 1929-39, 2014 Sep 01.
Article
em En
| MEDLINE
| ID: mdl-25184679
ABSTRACT
Cell type-specific conditional activation of oncogenic K-Ras is a powerful tool for investigating the cell of origin of adenocarcinomas in the mouse lung. Our previous studies showed that K-Ras activation with a CC10(Scgb1a1)-CreER driver leads to adenocarcinoma in a subset of alveolar type II cells and hyperplasia in the bronchioalveolar duct region. However, no tumors develop in the bronchioles, although recombination occurs throughout this region. To explore underlying mechanisms, we simultaneously modulated either Notch signaling or Sox2 levels in the CC10+ cells along with activation of K-Ras. Inhibition of Notch strongly inhibits adenocarcinoma formation but promotes squamous hyperplasia in the alveoli. In contrast, activation of Notch leads to widespread Sox2+, Sox9+, and CC10+ papillary adenocarcinomas throughout the bronchioles. Chromatin immunoprecipitation demonstrates Sox2 binding to NOTCH1 and NOTCH2 regulatory regions. In transgenic mouse models, overexpression of Sox2 leads to a significant reduction of Notch1 and Notch2 transcripts, while a 50% reduction in Sox2 leads to widespread papillary adenocarcinoma in the bronchioles. Taken together, our data demonstrate that the cell of origin of K-Ras-induced tumors in the lung depends on levels of Sox2 expression affecting Notch signaling. In addition, the subtype of tumors arising from type II cells is determined in part by Notch activation or suppression.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Adenocarcinoma
/
Genes ras
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Receptores Notch
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Fatores de Transcrição SOXB1
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Neoplasias Pulmonares
Tipo de estudo:
Prognostic_studies
Limite:
Animals
Idioma:
En
Revista:
Genes Dev
Assunto da revista:
BIOLOGIA MOLECULAR
Ano de publicação:
2014
Tipo de documento:
Article