Abstract
Malignant melanoma, characterized by its ability to metastasize to other organs, is responsible for 90% of skin cancer mortality. To investigate alterations in the cellular metabolome and lipidome related to melanoma metastasis, gas chromatography-mass spectrometry (GC-MS) and direct infusion-mass spectrometry (DI-MS)-based metabolic and lipidomic profiling were performed on extracts of normal human melanocyte (HEMn-LP), low metastatic melanoma (A375, G361), and highly metastatic melanoma (A2058, SK-MEL-28) cell lines. In this study, metabolomic analysis identified aminomalonic acid as a novel potential biomarker to discriminate between different stages of melanoma metastasis. Uptake and release of major metabolites as hallmarks of cancer were also measured between high and low metastatic melanoma cells. Lipid analysis showed a progressive increase in phosphatidylinositol (PI) species with saturated and monounsaturated fatty acyl chains, including 16:0/18:0, 16:0/18:1, 18:0/18:0, and 18:0/18:1, with increasing metastatic potential of melanoma cells, defining these lipids as possible biomarkers. In addition, a partial-least-squares projection to latent structure regression (PLSR) model for the prediction of metastatic properties of melanoma was established, and central metabolic and lipidomic pathways involved in the increased motility and metastatic potential of melanoma cells were identified as therapeutic targets. These results could be used to diagnose and control of melanoma metastasis.
Highlights
Melanoma is by far the most lethal form of cutaneous cancer because of ability to metastasize to other organs[1]
Metabolic changes related to metastasis of melanoma in a C57BL/6J mouse model and murine melanoma cell lines (Tm1, Tm5, and B16F10) have been identified by nuclear magnetic resonance (NMR)-based metabolic profiling[18,19,20,21], and a fatty acids and phospholipid group analysis of high- and low-metastatic B16 melanoma cell lines by gas-liquid chromatography equipped with dual-flame ionization detectors has been performed[22]
In the case of purines, hypoxanthine was markedly upregulated in two melanoma cell lines relative to that in normal cells, whereas inosine and guanine were highest in the A2058 cell line
Summary
Melanoma is by far the most lethal form of cutaneous cancer because of ability to metastasize to other organs[1]. Overexpression of human epidermal growth factor receptor 3 (HER3) has been associated with melanoma metastases, and suppression of HER3 inhibits melanoma cell proliferation, migration, and invasion[7]. Potential biomarkers such as VEGF, MIA, and CXCL1 are known to play a critical role in remodeling of the tumor microenvironment during metastasis of melanoma, and increased levels of these proteins are correlated with more advanced stages of cancer[8,9,10]. There has been no research focused on comparing changes in metabolites and individual lipid species in human melanoma cell lines with low and high metastatic potential with mass spectrometric-based approaches. The results were used to develop a partial-least-squares projection to latent structure regression (PLSR) prediction model and identify novel biomarkers for the different metastatic stages of melanoma
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