Human genetic polymorphisms (SNPs) of nicotinic receptors subunits alpha3, alpha5 and beta4 are linked to COPD and lung cancer by very robust human Genome-wide Association Studies (GWAS). Some of these SNPs, particularly of the alpha5 subunit, also increase smoking levels. However, there is no information on the potential role of these SNPs, also expressed in airway epithelial cells, with regards to the functional alterations of these cells and carcinogenesis. The aim of the project is to determine the smoking independent contribution of the alpha5 SNPs on the development of preneoplastic lesions and carcinomas of the lung. We have published a paper in Nature Communications (2021) showing that the presence of a5SNP in a “humanised” mouse model, and also in patient samples, leads to phenotypes characterised as “COPD”, chronic obstructive pulmonary disease, without any exposure to cigarette smoke or nicotine. COPD is typically associated with further progression towards lung cancer.
We now pursue our analysis in a lung cancer model, the k-ras L1 mouse. Crossing it with the a5SNP line we have established double-transgenic mice. The aim of this project is to elucidate the role of the a5SNP line in the development of lung tumors by the quantification of tumour load in the different lines and investigating the underlying mechanisms and the altered signaling pathways in the lungs of these mice through a comprehensive transcriptome analysis.
