Journal Article

Enhanced Lyn Activity Causes Severe, Progressive Emphysema and Lung Cancer

Anderson, Gary P., Gottschalk, Timothy A., L’Estrange-Stranieri, Elan, McQualter, Jonathan L., Wickramasinghe, Lakshanie C., Raftery, April L., Tsantikos, Evelyn, O’Brien, Caitlin A., Hibbs, Margaret L.

2023

Overview

The epidemiological patterns of incident chronic obstructive pulmonary disease (COPD) and lung adenocarcinoma are changing, with an increasing fraction of disease occurring in patients who are never-smokers or were not exposed to traditional risk factors. However, causative mechanism(s) are obscure. Overactivity of Src family kinases (SFKs) and myeloid cell–dependent inflammatory lung epithelial and endothelial damage are independent candidate mechanisms, but their pathogenic convergence has not been demonstrated. Here we present a novel preclinical model in which an activating mutation in Lyn, a nonreceptor SFK that is expressed in immune cells, epithelium, and endothelium—all strongly implicated in the pathogenesis of COPD—causes spontaneous inflammation, early-onset progressive emphysema, and lung adenocarcinoma. Surprisingly, even though activated macrophages, elastolytic enzymes, and proinflammatory cytokines were prominent, bone marrow chimeras formally demonstrated that myeloid cells were not disease initiators. Rather, lung disease arose from aberrant epithelial cell proliferation and differentiation, microvascular lesions within an activated endothelial microcirculation, and amplified EGFR (epidermal growth factor receptor) expression. In human bioinformatics analyses, LYN expression was increased in patients with COPD and was correlated with increased EGFR expression, a known lung oncogenic pathway, and LYN was linked to COPD. Our study shows that a singular molecular defect causes a spontaneous COPD-like immunopathology and lung adenocarcinoma. Furthermore, we identify Lyn and, by implication, its associated signaling pathways as new therapeutic targets for COPD and cancer. Moreover, our work may inform the development of molecular risk screening and intervention methods for disease susceptibility, progression, and prevention of these increasingly prevalent conditions.

• Publisher: Oxford University Press
• Subject: Adenocarcinoma / Adenocarcinoma of Lung - genetics / Age / Cancer / Cell differentiation / Cell proliferation / Chimeras / Chronic obstructive pulmonary disease / Emphysema / Endothelium / Epidermal growth factor receptors / Epithelial cells / Epithelium / ErbB Receptors - metabolism / Humans / Inflammation / Lung cancer / Lung diseases / Lung Neoplasms - genetics / Macrophages / Microvasculature / Myeloid cells / Obstructive lung disease / Pulmonary Disease, Chronic Obstructive - metabolism / Pulmonary Emphysema - genetics / Pulmonary fibrosis / src-Family Kinases - metabolism