Mitochondrial-Related Gene Expression and Macrophage Signatures in Non-Small Cell Lung Cancer, Including Patients with Emphysema as Co-Morbidity

Abstract

Objective: Our aim is to determine whether mitochondrial dysfunction is a contributing factor to the increased risk of non-small cell lung carcinoma (NSCLC) in COPD patients. Methods:The clinical relevance of mitochondrial-related gene expression in lung cancer was determined using transcriptomic data from more than 1000 human NSCLC samples. Immunohistochemistry was then used to study cell type specific expression of the relevant mitochondrial-related protein in normal and cancerous lung tissue. Gene set variation analysis (GSVA) was applied in NSCLC datasets to determine the relative expression of specific macrophage transcriptomic signatures. Results:The expression of 33 mitochondrial-related genes was correlated with NSCLC patient survival. We studied further the expression of PGAM5 and FUNDC1, which are regulators of mitochondrial degradation (mitophagy). In background lung tissue, PGAM5 and FUNDC1 were only expressed in alveolar macrophages, with highest expression in smokers with emphysema compared to healthy smokers and non-smokers. In cancerous tissue, only the malignant epithelial cells and associated macrophages at the periphery of the cancer, expressed PGAM5 and FUNDC1. PGAM5 was also expressed in pre-neoplastic epithelium (squamous dysplasia and carcinoma in situ). There was no difference in expression in cancer tissue between the emphysema, healthy smokers and non-smokers group. Macrophages at the edge of the cancer from emphysema patients had a trend towards higher expression of PGAM5 and FUNDC1 compared to those from the other groups. There was a significant correlation between PGAM5 expression in cancer tissue and 9 out of 49 previously defined macrophage transcriptomic signatures with one (module 22) associated with patient survival (p<0.05). Conclusion:PGAM5 is expressed in pre-neoplastic tissue and NSCLC, but not in normal epithelium. The association between PGAM5 expression and lung cancer outcome may be mediated by the induction of specific macrophage phenotypes.