S58 Beta-Catenin determines tracheal cell fate and squamous lung cancer progression by modulating intercellular adhesiveness

    loading  Checking for direct PDF access through Ovid

Abstract

Human lung cancers including squamous cell carcinoma (SCC) are a leading cause of death, and while 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 stem cell fate and subsequent SCC progression. In a cohort of preinvasive SCCs we established that elevated basal stem 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 stem cells delayed normal airway repair while basal cell-specific β-catenin activation increased cell proliferation, directed differentiation, and promoted an epithelial-to-mesenchymal transition (EMT) that included increased Snail transcription and reduced E-cadherin-mediated adhesiveness. These effects were 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 this data shows that airway stem cell β-catenin modulates cell adhesiveness to determine cell fate and its mis-expression is a key step in the development of human lung cancer.

Related Topics

    loading  Loading Related Articles