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. Copyright © 2012 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Gpr177 regulates pulmonary vasculature development

“…These findings are consistent with the crucial roles of Wnt signaling in lung development and maintenance (Morrisey and Hogan, 2010;Giangreco et al, 2012). Conditional deletion of epithelial Gpr177 affects lung branching, epithelial differentiation and pulmonary vasculature morphogenesis.…”

Building and maintaining the epithelium of the lung

“…Functional analysis of isolated basal cells suggests significant heterogeneity in their capacity for clonal expansion and generation of differentiating progeny in vitro (39,41,45). A number of signaling molecules and pathways regulate the behavior of basal cells including TRP63, SOX2, WNT, and Notch (24,(46)(47)(48)(49). Interestingly, Notch signaling promotes basal cell differentiation into luminal progeny (49), suggesting that interactions between basal cells and their luminal counterparts may determine whether daughter cells undergo renewal (generate more basal cells) or differentiation (generate luminal cells).…”

Irradiated fibroblasts promote epithelial–mesenchymal transition and HDGF expression of esophageal squamous cell carcinoma

“…E-cadherin has dual functions in epithelial cells: as cellecell adhesion molecule and as negative regulator of the canonical WNT signaling cascade, in particular of its central mediator b-catenin [26]. On the contrary, b-catenin activation increases cell proliferation, directed differentiation and promoted elements of early EMT, including increased Snail transcription and reduced Ecadherin expression [27]. Nuclear b-catenin induces a gene expression pattern favoring tumor invasion, and mounting evidence indicates multiple reciprocal interactions of E-cadherin and b-catenin with EMT-inducing transcriptional repressors to stabilize an invasive mesenchymal phenotype of epithelial tumor cells [26].…”