Rôle du récepteur nicotinique dans la dépendance tabagique et le carcinome bronchique – NICOPNEUMOTINE

The project presented here is a truly collaborative effort between two laboratories with complementary expertise. The basic issue addressed is the implication of the nicotinic receptor (nAChR) in nicotine dependence, leading to lung cancers. Lung cancers are among the most common human malignancies. A large amount of research effort is being put into understanding the genetic and molecular bases of this disease. Smoking has been proven to be a major risk factor. However, a large percentage of human lung cancer patients has never smoked, and the question arises as to the other factors implicated in the disease. In April 2008, three independent consortia published their findings on Whole Genome Association Studies (WGAS) implicating a locus on human chromosome 15q25 in the susceptibility to lung cancer. The study by Huang et al. showed that this susceptibility is not dependent on smoking behaviour, and they did identify polymorphisms also in non-smokers4. This locus encompasses three genes for subunits of the nicotinic acetylcholine receptor (nAChR), the subunits coding for '3, '5, and '4, also designated CHRNA3, CHRNA5 and CHRNB4, respectively. The study from Iceland came to the conclusion that the polymorphisms identified at the same locus 15q25 correlate with smoking behaviour, thus postulating an implication of these subunits in nicotine addiction. These three studies were the first to implicate nAChR genes in the susceptibility to lung cancer. The aim of the present project is to dissect, in mouse models and human lung tissue, the implication of these different nicotinic subunits in the events leading to carcinoma. We propose to associate complementary expertise from two laboratories: The Research Unit headed by Uwe Maskos at the Pasteur Institute is a leading laboratory implicated in in vivo studies of nicotinic receptor physiology and function, carrying out research from the molecular level to behaviour. The INSERM Unit headed by Philippe Birembaut has a long track record in research on the physiology of the human respiratory epithelium, and in mouse and in vitro models. Combining approaches from both laboratories provides thus a unique opportunity to further our understanding of the pathogenesis of lung carcinoma, and the potential discovery and development of cholinergic-nicotinic medication to combat this disease. The proposed project will allow to decide first of all, in animal models, whether the ACNA3, ACNA5 and ACNB4 subunits are indeed important in nicotine reinforcement. At the same time, the working hypothesis will be tested whether their sole mutant expression in the respiratory epithelium is sufficient for cancer induction. The project combines an in-depth study of mouse models with access to clinical samples. Working directly on human tissue, with all ethical aspects duly respected, will allow us to directly test the polymorphisms described in human patients in human tissue. Lentiviral vectors (LVs) have been used by our team extensively to express or knock-down (KD) nAChR subunits in vivo. LVs will now be created to express, over-express and re-press the human subunits in tissue derived from biopsies, i.e. in cells derived from human lung tissue, in an inducible fashion.