title: β-Catenin determines upper airway progenitor cell fate and preinvasive squamous lung cancer progression by modulating epithelial-mesenchymal transition.
abstract: Human lung cancers, including squamous cell carcinoma (SCC) are a leading cause of death and, whilst evidence suggests that basal stem cells drive SCC initiation and progression, the mechanisms regulating these processes remain unknown. In this study we show that β-catenin signalling regulates basal progenitor cell fate and subsequent SCC progression. In a cohort of preinvasive SCCs we established that elevated basal cell β-catenin signalling is positively associated with increased disease severity, epithelial proliferation and reduced intercellular adhesiveness. We demonstrate that transgene-mediated β-catenin inhibition within keratin 14-expressing basal cells delayed normal airway repair while basal cell-specific β-catenin activation increased cell proliferation, directed differentiation and promoted elements of early epithelial-mesenchymal transition (EMT), including increased Snail transcription and reduced E-cadherin expression. These observations are recapitulated in normal human bronchial epithelial cells in vitro following both pharmacological β-catenin activation and E-cadherin inhibition, and mirrored our findings in preinvasive SCCs. Overall, the data show that airway basal cell β-catenin determines cell fate and its mis-expression is associated with the development of human lung cancer.
authors.affiliation: Centre for Respiratory Research, University College London, UK.
authors.forename: Adam
authors.initials: A
authors.lastname: Giangreco
authors.forename: Liwen
authors.initials: L
authors.lastname: Lu
authors.forename: Charles
authors.initials: C
authors.lastname: Vickers
authors.forename: Vitor Hugo
authors.initials: VH
authors.lastname: Teixeira
authors.forename: Karen R
authors.initials: KR
authors.lastname: Groot
authors.forename: Colin R
authors.initials: CR
authors.lastname: Butler
authors.forename: Ekaterina V
authors.initials: EV
authors.lastname: Ilieva
authors.forename: P Jeremy
authors.initials: PJ
authors.lastname: George
authors.forename: Andrew G
authors.initials: AG
authors.lastname: Nicholson
authors.forename: Elizabeth K
authors.initials: EK
authors.lastname: Sage
authors.forename: Fiona M
authors.initials: FM
authors.lastname: Watt
authors.forename: Sam M
authors.initials: SM
authors.lastname: Janes
mesh_terms: D053687:Adult Stem Cells / Q000378:metabolism / Q000473:pathology*; D000818:Animals; D014408:Biomarkers, Tumor / Q000378:metabolism; D015820:Cadherins / Q000235:genetics / Q000378:metabolism; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D002461:Cell Line, Transformed; D019070:Cell Lineage / Q000502:physiology; D049109:Cell Proliferation; D015331:Cohort Studies; D018450:Disease Progression; D058750:Epithelial-Mesenchymal Transition; D005260:Female; D006801:Humans; D053547:Keratin-14 / Q000235:genetics / Q000378:metabolism; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009361:Neoplasm Invasiveness; D015398:Signal Transduction; D000071250:Snail Family Transcription Factors; D014132:Trachea / Q000378:metabolism / Q000473:pathology*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D051176:beta Catenin / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
chemical_list: D014408:Biomarkers, Tumor; C495270:CTNNB1 protein, human; D015820:Cadherins; D053547:Keratin-14; C507446:Krt14 protein, mouse; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors; D051176:beta Catenin
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