title: The cell of origin and subtype of K-Ras-induced lung tumors are modified by Notch and Sox2.
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.
authors.affiliation: Department of Surgery, Duke Medicine, Durham, North Carolina 27710, USA;
authors.forename: Xia
authors.initials: X
authors.lastname: Xu
authors.affiliation: Department of Surgery, Duke Medicine, Durham, North Carolina 27710, USA;
authors.forename: Lingling
authors.initials: L
authors.lastname: Huang
authors.affiliation: Department of Surgery, Duke Medicine, Durham, North Carolina 27710, USA;
authors.forename: Christopher
authors.initials: C
authors.lastname: Futtner
authors.affiliation: Department of Surgery, Duke Medicine, Durham, North Carolina 27710, USA;
authors.forename: Brian
authors.initials: B
authors.lastname: Schwab
authors.affiliation: Department of Surgery, Duke Medicine, Durham, North Carolina 27710, USA;
authors.forename: Rishi R
authors.initials: RR
authors.lastname: Rampersad
authors.affiliation: Department of Toxicology, Tsingua University, Beijing 100084, China;
authors.forename: Yun
authors.initials: Y
authors.lastname: Lu
authors.affiliation: Department of Pathology, Duke Medicine, Durham, North Carolina 27710, USA;
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Sporn
authors.affiliation: Department of Cell Biology, Duke Medicine, Durham, North Carolina 27710, USA.
authors.forename: Brigid L M
authors.initials: BL
authors.lastname: Hogan
authors.affiliation: Department of Surgery, Duke Medicine, Durham, North Carolina 27710, USA; mark.onaitis@dm.duke.edu.
authors.forename: Mark W
authors.initials: MW
authors.lastname: Onaitis
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics* / Q000473:pathology*; D000818:Animals; D015972:Gene Expression Regulation, Neoplastic; D011905:Genes, ras / Q000235:genetics*; D008175:Lung Neoplasms / Q000235:genetics* / Q000473:pathology*; D051379:Mice; D008822:Mice, Transgenic; D011485:Protein Binding; D011650:Pulmonary Alveoli / Q000473:pathology; D051880:Receptors, Notch / Q000235:genetics / Q000378:metabolism*; D055748:SOXB1 Transcription Factors / Q000378:metabolism*; D015398:Signal Transduction; D015533:Transcriptional Activation / Q000235:genetics
chemical_list: D051880:Receptors, Notch; D055748:SOXB1 Transcription Factors; C527783:Sox2 protein, mouse
keywords: K-Ras; Notch; Sox2; lung cancer