Succony, LJ; (2017) Defining the role of LRIG1 dependent EGFR signalling on airway homeostasis and lung cancer development. Doctoral thesis , UCL (University College London).

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Abstract

Aberrations of EGFR signalling drive cancer development. In squamous cell lung cancer, EGFR is overexpressed. LRIG1 is a negative regulator of EGFR and patient pre-invasive squamous cell lung cancer samples show LRIG1 loss, suggesting involvement in early disease pathogenesis. In skin and gut homeostasis, LRIG1 regulates stem cells. In the upper airway, basal cells act as stem cells and are the putative origin of squamous cell lung cancer. I hypothesise LRIG1 has a key role in the airway homeostasis and its loss tilts this towards pre-invasive squamous cell lung cancer development. Lrig1 EGFP-ires-CreERT2 mice delineated airway LRIG1 expression. Flow sorted LRIG1-positive and -negative murine basal cells were used in 2D and 3D colony-forming, spheroid and proliferation assays. A murine squamous cell lung cancer model was set up through application of N-Nitrosotris-(2-chloroethyl)urea (NTCU). Pre-invasive lesions and tumour development were compared between wild-type (WT), LRIG1-heterozygous and LRIG1-null animals. Human basal cells obtained from bronchoscopy were sorted according to LRIG1 expression and used directly in colony-forming assays or maintained in primary culture to assess the effect of shRNA knockdown of LRIG1. LRIG1 is expressed by 50% of airway basal cells. LRIG1-expressing murine basal cells exhibit increased colony-forming capacity (p=0.0133), spheroid formation (p=0.0020) and proliferation (p=0.0011) compared to LRIG1-negative cells. Similarly, LRIG1-expressing human airway basal cells isolated from endobronchial brush biopsy samples exhibit increased colony-forming capacity (p=0.0067) and proliferation (p=0.0153). Topical application of NTCU to mice recapitulates the development of human pre-invasive and squamous cell lung cancer lesions after 23 weeks. Results show lesions in LRIG1-null mice to be larger than those of WT animals. shRNA knockdown of LRIG1 in cultured human airway basal cells alters cell phenotype, leading to increased colony-forming efficiency and greater proliferation at cell confluence. LRIG1 has an important role in stem cell homeostasis of the human and murine airway epithelium. Loss of LRIG1 promotes lesion development in a murine squamous cell lung cancer mouse model and alters behaviour of human epithelial cells in culture, indicating a potential target for the treatment of squamous cell lung cancer in humans.

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