PT -期刊文章盟Succony劳拉盟——国美z-López, Sandra AU - Pennycuick, Adam AU - Alhendi, Ahmed S. N. AU - Davies, Derek AU - Clarke, Sarah E. AU - Gowers, Kate H.C. AU - Wright, Nicholas A. AU - Jensen, Kim B. AU - Janes, Sam M. TI - Lrig1 expression identifies airway basal cells with high proliferative capacity and restricts lung squamous cell carcinoma growth AID - 10.1183/13993003.00816-2020 DP - 2021 Jan 01 TA - European Respiratory Journal PG - 2000816 4099 - //www.qdcxjkg.com/content/early/2021/07/29/13993003.00816-2020.short 4100 - //www.qdcxjkg.com/content/early/2021/07/29/13993003.00816-2020.full AB - Lung squamous cell carcinoma (LUSC) accounts for a significant proportion of cancer deaths worldwide, and is preceded by the appearance of progressively disorganised pre-invasive lesions in the airway epithelium. Yet the biological mechanisms underlying progression of pre-invasive lesions into invasive LUSC are not fully understood. LRIG1 is downregulated in pre-invasive airway lesions and invasive LUSC tumours and this correlates with decreased lung cancer patient survival.Using an Lrig1 knock-in reporter mouse and human airway epithelial cells collected at bronchoscopy, we show that during homeostasis LRIG1 is heterogeneously expressed in the airway epithelium. In basal airway epithelial cells, the suspected cell of origin of LUSC, LRIG1 identifies a subpopulation of progenitor cells with higher in vitro proliferative and self-renewal potential in both the mouse and human. Using the N-nitroso-tris-chloroethylurea (NTCU)-induced murine model of LUSC, we find that Lrig1 loss-of-function leads to abnormally high cell proliferation during the earliest stages of pre-invasive disease and to the formation of significantly larger invasive tumours, suggesting accelerated disease progression.Together, our findings identify LRIG1 as a marker of basal airway progenitor cells with high proliferative potential and as a regulator of pre-invasive lung cancer progression. This work highlights the clinical relevance of LRIG1 and the potential of the NTCU-induced LUSC model for functional assessment of candidate tumour suppressors and oncogenes.FootnotesThis manuscript has recently been accepted for publication in the European Respiratory Journal. It is published here in its accepted form prior to copyediting and typesetting by our production team. After these production processes are complete and the authors have approved the resulting proofs, the article will move to the latest issue of the ERJ online. Please open or download the PDF to view this article.Conflict of interest: Dr. Succony reports grants from Wellcome Trust, grants from Cancer Research UK, during the conduct of the study.Conflict of interest: Dr. Gómez López reports grants from The Royal Society, during the conduct of the study.Conflict of interest: Dr. Pennycuick reports grants from Wellcome Trust, during the conduct of the study; In addition, Dr. Pennycuick has a patent United Kingdom Patent Application No. 1819452.2 pending.Conflict of interest: Dr. Alhendi has nothing to disclose.Conflict of interest: Dr. Davies has nothing to disclose.Conflict of interest: Dr. Clarke reports grants from NIHR UCLH BRC, during the conduct of the study.Conflict of interest: Dr. Gowers has nothing to disclose.Conflict of interest: Dr. Wright reports grants from Cancer Research UK, outside the submitted work.Conflict of interest: Dr. Jensen has nothing to disclose.Conflict of interest: Dr. Janes reports grants from Wellcome, during the conduct of the study; personal fees from Jansen, grants from GRAIL Inc, personal fees from Astra Zeneca, outside the submitted work.