Accelerated, untargeted metabolomics analysis of cutaneous T‐cell lymphoma reveals metabolic shifts in plasma and tumor adjacent skins of xenograft mice

Abstract

Cutaneous T-cell lymphoma (CTCL) is a heterogeneous group of skin-homing T-cell neoplasms. Clinical management is stage based but diagnosis and prognosis could be extremely challenging. The presented study aims to explore the metabolic profiling of CTCL by an accelerated untargeted metabolomics data analysis tool "Mummichog" to facilitate the discoveries of potential biomarkers for clinical early stage diagnosis, prognosis, and treatments in CTCL. Ultra high-performance liquid chromatography-quadrupole time-of-flight-based untargeted metabolomics were conducted on the skin and plasma of CTCL mice. It showed that the metabolism of skin changed greatly versus control samples in the development of CTCL. Increased l-glutamate and decreased adenosine monophosphate were the most essential metabolic features of CTCL tumor and tumor adjacent skins. Unique metabolism changes in tumor adjacent non-involved skin tissues (ANIT) occurred in the progress of carcinogenesis, including upregulated cytidine-5'-triphosphate, aberrant biosynthesis of prostaglandins, pyrimidine, mevalonate pathway, and tryptophan degradation. Sharply elevated 5-phospho-α-d-ribose 1-diphosphate (PRPP) marked the final state of tumor in CTCL. In the plasma, systematic shifts in corticosterone, sphingolipid, and ceramide metabolism were found. These uncovered aberrant metabolites and metabolic pathways suggested that the metabolic reprogramming of PRPP in tumor tissues may cause the disturbance of cytidine and uridine metabolic homeostasis in ANIT. Accumulative cytidine-5'-triphosphate in ANIT may exert positive feedback on the PRPP level and leads to CTCL further development. In addition, the accelerated data analysis tool "Mummichog" showed good practicability and can be widely used in high-resolution liquid chromatography mass spectrometry-based untargeted metabolomics.

Current Knowledge in Skin Metabolomics: Updates from Literature Review

“…Several other dermatological conditions have recently been studied from the metabolomic point of view, including inflammatory infectious and neoplastic conditions [ 80 , 89 , 104 , 106 ]. Increased levels of L-glutamate have been found in skin samples of cutaneous T cell lymphomas and adjacent skin, together with decreased adenosine monophosphate [ 65 ]. Several alterations in fatty acid metabolism have been associated with Lyme’s disease [ 39 , 76 ].…”

“Next top” mouse models advancing CTCL research

“…The dual PI3K/mTOR inhibitor PF-502 extends survival, suggesting its promise in treating CTCL ( Bresin et al, 2020 ). Additionally, metabolic analysis of CTCL-transplanted mice has identified changes in L-glutamate and adenosine monophosphate, offering insight into CTCL biomarkers ( Le et al, 2018 ).…”

Accelerated, untargeted metabolomics analysis of cutaneous T‐cell lymphoma reveals metabolic shifts in plasma and tumor adjacent skins of xenograft mice

“…The grant number in the Acknowledgements of Le et al is incorrect. The study was funded by a grant from National Nature Science Foundation of China (No.…”