Proteome Signatures in Non-Small Cell Lung Cancer

Lung cancer is one of the most common cancers worldwide, and is the top cause of cancer-related death in both men and women. Non-small cell lung cancer (NSCLC) accounts for 85% of lung cancers and is subdivided into two major histological subtypes: adenocarcinoma (ADC) and squamous cell carcinoma (SCC). While the genomic and transcriptomic landscapes of NSCLC ADC and SCC have been well portrayed, the proteome of NSCLC is less characterized although expected to have a pronounced and direct effect on cancer phenotype. In my PhD study, I used mass spectrometry-based quantitative shotgun proteomics approaches to characterize proteome signatures related to NSCLC histological subtypes and patient tumor engraftment, the later of which correlates with prognosis. I first demonstrated that proteomes of human lung ADC and SCC patient tumor-derived xenografts could be resolved and a multi-protein histology signature comprised of various components of the epithelial barrier and metabolism enzymes was identified and validated. The ability of primary NSCLC to engraft in immuno-compromised mice and form a stable patient-derived xenograft is a poor prognosis indicator, suggesting that engraftment selects for aggressive aspects of the cancer phenotype linked to disease progression, which is not understood at a molecular level. I found that proteomes were different between tumors that could or could not engraft, which highlighted a metabolism protein, mitochondrial aconitase 2 (ACO2), as the strongest predictor of engraftment. Consistent with lower ACO2 protein level measured in engrafting tumors, weak ACO2 protein expression level correlated with poor outcome in an independent cohort of NSCLC patients. Furthermore, ectopic expression of ACO2 in a NSCLC cell line suppressed cell proliferation in vitro and in vivo. My work illustrates the power of proteomics approaches to uncover clinically relevant cancer signatures not revealed by genomic and transcriptomic methods and expands our understanding of proteome remodeling in cancers.Ph.D.2019-11-16 00:00:0