title: Wnt/β-catenin signaling accelerates mouse lung tumorigenesis by imposing an embryonic distal progenitor phenotype on lung epithelium.
abstract: Although mutations in Kras are present in 21% of lung tumors, there is a high level of heterogeneity in phenotype and outcome among patients with lung cancer bearing similar mutations, suggesting that other pathways are important. Wnt/β-catenin signaling is a known oncogenic pathway that plays a well-defined role in colon and skin cancer; however, its role in lung cancer is unclear. We have shown here that activation of Wnt/β-catenin in the bronchiolar epithelium of the adult mouse lung does not itself promote tumor development. However, concurrent activation of Wnt/β-catenin signaling and expression of a constitutively active Kras mutant (KrasG12D) led to a dramatic increase in both overall tumor number and size compared with KrasG12D alone. Activation of Wnt/β-catenin signaling altered the KrasG12D tumor phenotype, resulting in a phenotypic switch from bronchiolar epithelium to the highly proliferative distal progenitors found in the embryonic lung. This was associated with decreased E-cadherin expression at the cell surface, which may underlie the increased metastasis of tumors with active Wnt/β-catenin signaling. Together, these data suggest that activation of Wnt/β-catenin signaling can combine with other oncogenic pathways in lung epithelium to produce a more aggressive tumor phenotype by imposing an embryonic distal progenitor phenotype and by decreasing E-cadherin expression.
authors.affiliation: Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors.forename: Eugenia C
authors.initials: EC
authors.lastname: Pacheco-Pinedo
authors.forename: Amy C
authors.initials: AC
authors.lastname: Durham
authors.forename: Kathleen M
authors.initials: KM
authors.lastname: Stewart
authors.forename: Ashley M
authors.initials: AM
authors.lastname: Goss
authors.forename: Min Min
authors.initials: MM
authors.lastname: Lu
authors.forename: Francesco J
authors.initials: FJ
authors.lastname: Demayo
authors.forename: Edward E
authors.initials: EE
authors.lastname: Morrisey
mesh_terms: D000818:Animals; D001980:Bronchi / Q000378:metabolism; D015820:Cadherins / Q000378:metabolism; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism; D004847:Epithelial Cells / Q000166:cytology; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008168:Lung / Q000378:metabolism; D008175:Lung Neoplasms / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D010641:Phenotype; D015398:Signal Transduction; D013234:Stem Cells / Q000166:cytology*; D051153:Wnt Proteins / Q000378:metabolism*
chemical_list: D015820:Cadherins; D051153:Wnt Proteins