Lu, L.; (2011) EGFR and WNT/β-catenin signalling in airway homeostasis and repair. Doctoral thesis , UCL (University College London).

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Abstract

Lung cancers are a leading cause of death worldwide, and although there is some evidence that both Epidermal Growth Factor Receptor (EGFR) and Wnt/β-catenin signalling are involved in initiation and progression of this disease the molecular mechanisms regulating these processes remain poorly described. Here I show that deletion of LRIG1, an endogenous EGFR inhibitor, leads to epithelial hyperplasia in the murine airway and continued proliferation post confluence in vitro. This occurs via phosphorylation of EGFR and its downstream effector molecule ERK1/2. Human lung cancer cell lines lacking LRIG1 showed a reduction of proliferation on LRIG1 replacement. Using co-localisation experiments I have defined LRIG1 inhibition of density dependent growth occurs through LRIG1 forming a complex with EGFR and E-Cadherin at the cell confluence. Examination of matched human pre-invasive lung cancer lesions with normal airway from the same individuals delineated loss of LRIG1 supporting its role in the early stages of cancer development. I further show that β-catenin regulates epithelial cell phenotype in both normal airway stem cells and preinvasive lung cancers. β-catenin inhibition within keratin 14-expressing stem cells impairs airway repair whilst activation increases cell proliferation, directs lineage choice, and promotes an epithelial-to-mesenchymal transition that includes loss of cadherin-mediated adhesions and increased Twist and Snail transcription influencing both intercellular and cell-matrix adhesiveness. These findings were recapitulated in vitro both by pharmacological β-catenin activation and direct E-cadherin inhibition. Thus, β-catenin modulation of cadherin-dependent intercellular adhesions determines cell phenotype and its overexpression is a key early step in pre-invasive disease development.

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