Metabolomic profiling of human lung tumor tissues – nucleotide metabolism as a candidate for therapeutic interventions and biomarkers

Abstract

Although metabolomics has attracted considerable attention in the field of lung cancer (LC) detection and management, only a very limited number of works have applied it to tissues. As such, the aim of this study was the thorough analysis of metabolic profiles of relevant LC tissues, including the most important histological subtypes (adenocarcinoma and squamous cell lung carcinoma). Mass spectrometry‐based metabolomics, along with genetic expression and histological analyses, were performed as part of this study, the widest to date, to identify metabolic alterations in tumors of the most relevant histological subtypes in lung. A total of 136 lung tissue samples were analyzed and 851 metabolites were identified through metabolomic analysis. Our data show the existence of a clear metabolic alteration not only between tumor vs. nonmalignant tissue in each patient, but also inherently intrinsic changes in both AC and SCC. Significant changes were observed in the most relevant biochemical pathways, and nucleotide metabolism showed an important number of metabolites with high predictive capability values. The present study provides a detailed analysis of the metabolomic changes taking place in relevant biochemical pathways of the most important histological subtypes of LC, which can be used as biomarkers and also to identify novel targets.

Metabolomic, transcriptomic and genetic integrative analysis reveals important roles of adenosine diphosphate in haemostasis and platelet activation in non‐small‐cell lung cancer

“…Paired lung biopsy samples stored at −80 °C were sent to Metabolon for metabolomic profiling, as described previously (Moreno et al ., ). Technical procedures included sample preparation, QA/QC, liquid chromatography/mass spectrometry (LC/MS, LC/MS 2 ), GC/MS, accurate mass determination and MS/MS fragmentation, data extraction and quality assurance, compound identification and normalization.…”

“…More recently, Moreno et al . () observed significant changes in glucose, glutathione, lipid and nucleotide metabolism in tumours in comparison with the normal tissues. So far, Fahrmann et al .…”

“…Besides these molecular mutations, abnormal cellular metabolism is also a hallmark of lung cancer (Hanahan and Weinberg, ). As with other types of cancer, the metabolic profile of NSCLC has been characterized by upregulation of key metabolic pathways such as glycolysis (Fahrmann et al ., ), the TCA cycle (Fan et al ., ), Krebs cycle (Sellers et al ., ) and nucleotide metabolism (Moreno et al ., ). Unfortunately, specific metabolic biomarkers of tumorigenesis and potential treatment targets are not well established.…”

Interaction between DNA damage response, translation and apoptosome determines cancer susceptibility to TOP2 poisons

“…Etoposide and TOP2 poisons are highly efficacious chemotherapy agents. Yet, differences in resistance across tumors and the toxicity associated with such treatments undermines the risk/benefit ratio that this therapy can offer to individual patients 36, 37, 38, 39, 40, 41 . To overcome this, biomarkers for etoposide and doxorubicin response are necessary, but virtually non-existent.…”

A NOTCH added to metabolomics

“…the Warburg effect) lead to altered nucleotide metabolism, which in turn may indicate an opportunity for therapeutic perturbations. 3 Furthermore, metabolomics studies can benefit from advances within imaging, especially PET-based methods. 4 Likewise, metabolomics data are already being used in radiotherapy planning, as the dosage of radiation is made dependent on the metabolic features obtained from PET-FDG images.…”