LC-HRMS based approach to identify novel sphingolipid biomarkers in breast cancer patients

Abstract

perturbations in lipid metabolic pathways to meet the bioenergetic and biosynthetic requirements is a principal characteristic of cancer cells. Sphingolipids (SpLs) are the largest class of bioactive lipids associated to various aspects of tumorigenesis and have been extensively studied in cancer cell lines and experimental models. the clinical relevance of SpLs in human malignancies however is still poorly understood and needs further investigation. in the present study, we adopted a UHpLc-High resolution (orbitrap) Mass spectrometry (HRMS) approach to identify various sphingolipid species in breast cancer patients. A total of 49 SPLs falling into 6 subcategories have been identified. Further, integrating the multivariate analysis with metabolomics enabled us to identify an elevation in the levels of ceramide phosphates and sphingosine phosphates in tumor tissues as compared to adjacent normal tissues. the expression of genes involved in the synthesis of reported metabolites was also determined in local as well as TCGA cohort. A significant upregulation in the expression of CERK and SPHK1 was observed in tumor tissues in local and tcGA cohort. Sphingomyelin levels were found to be high in adjacent normal tissues. Consistent with the above findings, expression of SGMS1 in tumor tissues was downregulated in tcGA cohort only. clinical correlations of the selected metabolites and their performance as biomarkers was also evaluated. Significant ROC and positive correlation with Ki67 index highlight the diagnostic potential and clinical relevance of ceramide phosphates in breast cancer.Dysregulation of lipid homeostasis has become an established hallmark of cancer. The cancer cells exploit lipid metabolic pathways in order to fulfil their demand for energy as well as biosynthetic precursors. Aberrations in lipid metabolism thus affects numerous cellular processes such as cell growth, proliferation, differentiation and cell survival 1 . Sphingolipids (SPLs), apart from the inceptive view of being considered as mere structural components, have evolved as crucial regulators of myriads of cellular functions. The primary elements of sphingolipid metabolism such as ceramide, ceramide 1-phosphate and sphingosine 1-phosphate have recently emerged as key regulators in cancer cell growth, proliferation, survival, migration and drug resistance 2-4 . Numerous studies have described the elementary role of ceramide and sphingosine 1-phosphate rheostat in various types of cancers such as lung, breast and colon. However, these studies have provided the mechanistic details of sphingolipid metabolism in cancer cell lines and experimental models 5-7 , while their role in human malignancies is still poorly understood and needs further elucidation.Breast cancer continues to remain the most common malignancy among women worldwide 8 . The diagnosis rate of breast cancer among Indian females is as high as 25.8 per 100,000 women with a mortality rate of 12.7 per 100,000 women 9 . Despite advancement in diagnostic and therapeutic modalities, th...

Ceramide kinase mediates intrinsic resistance and inferior response to chemotherapy in triple‐negative breast cancer by upregulating Ras/ERK and PI3K/Akt pathways

“…It is interesting to note that the upregulation of CERK expression (tumor/normal > 2) is found only in some TNBC patients, with a significant association with chemoresistance (Table 1 ). Previous studies using cell models and publicly available microarray data show that elevated CERK expression is linked with metastatic breast cancer and increased risk of recurrence in patients with breast cancer [ 12 , 13 , 23 ]. Specifically, CERK overexpression is also associated with decreased recurrence-free survival in patients with ER-negative breast cancer [ 14 ].…”

Serum Untargeted UHPLC-HRMS-Based Lipidomics to Discover the Potential Biomarker of Colorectal Advanced Adenoma

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Effect of Helicobacter Pylori on Plasma Metabolic Phenotype in Patients With Gastric Cancer

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