Lung Function and Disease

Metabolic reprogramming has long been recognized as a hallmark of cancer. Metabolomics can help unravel the relationship between metabolic events and disease risk, progression, and response to treatment in all cancers including lung cancer, enabling the identification of more robust biomarkers for risk prediction, prognosis, and treatment response. The combination of multiple omics datasets is a particularly powerful approach in cancer research. 

Combining gene expression and metabolomics data from cancerous tissues and cell lines, researchers demonstrated that the glycolytic enzyme alpha-enolase (ENO1) is responsible for proliferation and metastasis in non-small cell lung cancer (NSCLC). These data helped clarify the role of ENO1 in increased glucose metabolism in NSCLC and identified this enzyme as a potential therapeutic target. Another multi-omics study combining transcriptomics, metabolomics, and genomics data from NSCLC tumors identified a role for adenosine diphosphate in promoting metastasis, identifying another potential therapeutic target in NSCLC. 

Metabolomics and gene expression analysis of tumors from animal models and tumor tissues from human patients also revealed activation of the hexosamine biosynthesis pathway (HBP) in a particularly aggressive subset of NSCLC (KRAS/LKB1 co-mutant). Inhibition of the HBP enzyme Glutamine-Fructose-6-Phosphate Transaminase 2 (GFPT2) slowed tumor cell growth in both in vitro and in vivo models, pointing to GFPT2 as a promising therapeutic target.

Fu Q, Liu Y, Fan Y et al. Alpha-enolase promotes cell glycolysis, growth, migration, and invasion in non-small cell lung cancer through FAK-mediated PI3K/AKT pathway. J Hematol Oncol. 2015;8. doi: 10.1186/s13045-015-0117-5

Kim J, Lee HM, Cai F. et al.The hexosamine biosynthesis pathway is a targetable liability in KRAS/LKB1-mutant lung cancer. Nat Metab. 2020;2(12). doi: 10.1038/s42255-020-00316-0

Metabolomics helps identify physiologic differences that can stratify patients and guide treatment approaches for disease subtypes. For example, acute respiratory distress syndrome has a variety of causes, which may be associated with different underlying immune involvement despite similar clinical presentation and pathological manifestation. Using metabolomics, researchers compared bacterial sepsis-induced ARDs and COVID-19-induced ARDs, identifying several therapeutically relevant pathways and highlighting the potential to use JAK inhibitors to improve outcomes in bacterial sepsis-induced ARDs. Additionally, the researchers used multi-omic networks to identify signatures of acute kidney injury and thrombocytosis associated with IL-17, MAPK, and TNF signaling pathways and cell adhesion molecules and suggested that combination therapy targeting two or more of these may prove beneficial.

Batra R, Whalen W, Alvarez-Mulett S, et al. Multi-omic comparative analysis of COVID-19 and bacterial sepsis-induced ARDS.. PLoS Pathog. 2022;18(9):e1010819. doi: 10.1371/journal.ppat.1010819

Metabolomics may be used to predict the chance of lung transplantation success by identifying biomarkers indicative both of healthier transplant organs and of increased damage during transplantation itself. Combining gene expression and metabolomics data on reperfused lungs, researchers determined that increased oxidative stress via purine metabolism is a significant metabolic event during reperfusion and may be an important indicator of ischemic reperfusion injury. These data suggest that approaches to reduce oxidative stress, potentially by targeting purine metabolism, may help reduce ischemic injury during lung transplantation. 

Metabolomics analysis of donor lungs undergoing ex vivo perfusion prior to transplantation revealed that a small collection of metabolites, including palmitoyl-sphingomyelin, 5-aminovalerate, decanoylcarnitine, N2-methylguanosine, 5-aminovalerate, oleamide, and decanoylcarnitine were highly correlated with transplantation outcomes. These data provide a window into potential biomarkers that can be used to identify transplant lungs that may be less successful and to develop approaches to improve these lungs’ conditions prior to transplantation. Similarly, another study used metabolomics to demonstrate that cold storage at 10oC preserved mitochondrial health and donor organ function, providing another mechanism for improving the likelihood of transplant success.

Baciu, C., Shin, J., Hsin, M. et al. Altered purine metabolism at reperfusion affects clinical outcome in lung transplantation. Thorax. 2023;78(3). doi: 10.1136/thoraxjnl-2021-217498

Hsin, M.K., Zamel, R., Cypel, M. et al. Metabolic Profile of Ex Vivo Lung Perfusate Yields Biomarkers for Lung Transplant Outcomes. Ann Surg. 2018;267(1). doi: 10.1097/SLA.0000000000002016

Ali A, Wang A, Ribeiro RV, et al. Static lung storage at 10°C maintains mitochondrial health and preserves donor organ function. Sci Transl Med. 2021;13(611):eabf7601. doi: 10.1126/scitranslmed.abf7601