Defining the role of Lrig1- dependent EGFR signalling pathway inhibition in airway homeostasis and lung cancer development. (360G-Wellcome-102781_Z_13_Z)

The EGFR pathway is important in cell division, proliferation, angiogenesis and apoptosis. Aberrations of this pathway occur in lung cancer, with increased activity one of the earliest changes seen in preinvasive squamous cell lung cancer. Lrig1 is a membrane- associated negative regulator of EGFR signalling and has recently been shown by the host laboratory to have a tumour suppressor role; it negatively regulates proliferation at cell-cell contact and is lost in preinvasive lung cancer but p resent in normal airway epithelium. Intriguingly I have shown Lrig1 is associated with known progenitor populations in developing murine airways. My proposal establishes the role of Lrig1 in airway homeostasis, development and repair and delineates how its loss results in cancer development. I hypothesise Lrig1 expression controls airway cell homeostasis and its loss is sufficient to initiate pre-invasive lung cancer My key objectives are:- 1. To delineate the role of Lrig1 expression in normal, repairing and cancerous human and murine airways 2. To determine the role of Lrig1 in airway homeostasis and lung cancer initiation 3. To identify the mechanisms by which Lrig1 regulates epithelial growth and cancer initiation, and to generate therapeutic candidates