Distinct Cancer-Promoting Stromal Gene Expression Depending on Lung Function

Rationale: Chronic obstructive pulmonary disease (COPD) is an independent risk factor for lung cancer, but the underlying molecular mechanisms are unknown. We hypothesized that lung stromal cells activate pathological gene expression programs supporting oncogenesis. Objective: To identify molecular mechanisms operating in the lung stroma that support development of lung cancer. Methods: Study subjects included patients with- or without- lung cancer across a spectrum of lung function. We conducted multi-omics analysis of non-malignant lung tissue to quantify the transcriptome, translatome and proteome. Measurements and Main Results: Cancer-associated gene expression changes predominantly manifested as alterations in the efficiency of mRNA translation modulating protein levels in the absence of corresponding changes in mRNA levels. The molecular mechanisms driving these cancer-associated translation programs differed based on lung function. In subjects with normal to mildly impaired lung-function, the mamma...