Threshold Effects of Plasma Methyl Donor Nutrients Status on High Lactate-Metabolomics Signatures of Metastatic Tumors in Non-Small-Cell Lung Cancer Patients

Lung cancer is the leading cause of cancer-related mortality in the worldwide. In non-small-cell lung cancers (NSCLC), metabolic reprogramming of lactate metabolism has been proposed as a key player in cancer metastasis. Nutritional status of methyl donors was associated with increased risks of lung cancers, yet their roles in lactate metabolism and metastatic NSCLC development remains unclear. The cross-sectional study recruited 100 NSCLC patients with selected 18 paired NSCLC tissues from National Taiwan University Hospital (NTUH), Taiwan. Plasma methyl donors levels (folate/free choline/betaine) of NSCLC patients and target metabolomics signatures of paired NSCLC tissues were analyzed by Liquid chromatography–mass spectrometry (LC/MS). Clinical data of NSCLC tissues were collected from the department of pathology in NTUH. Partial Least Squares Discriminant Analysis (PLSDA) revealed that metabolic signatures of tumor/non-tumor lung tissues were well segregated. The two major tumor metabolites signatures of metastatic NSCLC were lactate and glucose, the levels of which were high and low, respectively, with both metabolites displaying the two highest VIP scores. A correlation heatmap showed that tumor lactate levels were strongly associated with increased TCA metabolites (pyruvate, succinate, fumarate and malate) and anaplerotic amino acid levels (alanine and arginine), and inversely correlated with glycolytic metabolites (glucose and PEP). When stratifying plasma methyl donors status of 18 paired NSCLC tumors with metabolomics VIP scores, threshold levels of folate (≥6 ng/ml), free choline (≥9.78 μmol/L) and betaine (≥62.0 μmol/L) were associated with high lactate and low glucose signatures of NSCLC. In particular, plasma betaine was positively associated with tumor lactate (r = 0.51, P = 0.031); plasma lactate was positively associated with tumor glucose (r = 0.53, P = 0.023). Our data demonstrate that metastatic NSCLCs were signified with high-lactate metabolizing-metabolomics fingerprints which were modified by plasma methyl donors’ status with a differential threshold effect. This study was supported by the three-year grant from the Ministration of Science and Technology, Taiwan, ROC.