LRIG1 regulates cadherin‐dependent contact inhibition directing epithelial homeostasis and pre‐invasive squamous cell carcinoma development |
| |
| Authors: | ZhengQiang Yuan Trevor A Graham David Endesfelder Krishna Kolluri Noura Al‐Juffali Nicholas Hamilton Andrew G Nicholson Mary Falzon Maik Kschischo Charles Swanton Nicholas A Wright Bernadette Carroll Fiona M Watt Jeremy P George Kim B Jensen Adam Giangreco Sam M Janes |
| |
| Institution: | 1. Lungs for Living Research Centre, UCL Respiratory, University College London, , London, WC1E 6JF UK;2. Histopathology Laboratory, Cancer Research UK London Research Institute, , London, WC2A 3PX UK;3. Centre for Evolution and Cancer, UCSF Helen Diller Family Comprehensive Cancer Center, , San Francisco, CA, 94143‐0875 USA;4. University of Applied Sciences, , 53424 Remagen, Germany;5. Cancer Research UK London Research Institute, , London, WC2A 3LY UK;6. Department of Histopathology, Royal Brompton and Harefield NHS Foundation Trust, and National Heart and Lung Institute, Imperial College, , London, UK;7. Department of Histopathology, University College Hospital London, , London, UK;8. Centre for Digestive Diseases, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, , London, E1 2AD UK;9. Epithelial Cell Biology Laboratory, Cancer Research UK Cambridge Research Institute, , Cambridge, UK;10. Wellcome Trust – Medical Research Council Stem Cell Institute, Department of Oncology, University of Cambridge, , Cambridge, UK |
| |
| Abstract: | Epidermal growth factor receptor (EGFR) pathway activation is a frequent event in human carcinomas. Mutations in EGFR itself are, however, rare, and the mechanisms regulating EGFR activation remain elusive. Leucine‐rich immunoglobulin repeats‐1 (LRIG1), an inhibitor of EGFR activity, is one of four genes identified that predict patient survival across solid tumour types including breast, lung, melanoma, glioma, and bladder. We show that deletion of Lrig1 is sufficient to promote murine airway hyperplasia through loss of contact inhibition and that re‐expression of LRIG1 in human lung cancer cells inhibits tumourigenesis. LRIG1 regulation of contact inhibition occurs via ternary complex formation with EGFR and E‐cadherin with downstream modulation of EGFR activity. We find that LRIG1 LOH is frequent across cancers and its loss is an early event in the development of human squamous carcinomas. Our findings imply that the early stages of squamous carcinoma development are driven by a change in amplitude of EGFR signalling governed by the loss of contact inhibition. © 2012 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland. |
| |
| Keywords: | EGFR LRIG1 squamous cell carcinoma lung cancer pre‐invasive E‐cadherin cell‐cell contact |
|
|
