Abstract
Multiple myeloma (MM) is well-known for the development of drug resistance, leading to relapse. Therefore, finding novel treatment strategies remains necessary. By performing a lipidomics assay on MM patient plasma, we aimed to identify new targets. We observed a dysregulation in the sphingolipid metabolism, with the upregulation of several ceramides and downregulation of sphingomyelin. This imbalance suggests an increase in sphingomyelinase, the enzyme responsible for hydrolyzing sphingomyelin into ceramide. We confirmed the upregulation of acid sphingomyelinase (ASM) in primary MM cells. Furthermore, we observed an increase in ASM expression in MM cell lines treated with melphalan or bortezomib, as well as in their exosomes. Exosomes high in ASM content were able to transfer the drug-resistant phenotype to chemosensitive cells, hereby suggesting a tumor-protective role for ASM. Finally, inhibition of ASM by amitriptyline improved drug sensitivity in MM cell lines and primary MM cells. In summary, this study is the first to analyze differences in plasma lipid composition of MM patients and match the observed differences to an upregulation of ASM. Moreover, we demonstrate that amitriptyline is able to inhibit ASM and increase sensitivity to anti-myeloma drugs. This study, therefore, provides a rational to include ASM-targeting-drugs in combination strategies in myeloma patients.
Highlights
Multiple myeloma (MM) is a plasma cell malignancy in which the tumoral cells reside in the bone marrow
We found that the lipidome of peripheral plasma in myeloma patients differed from healthy plasma: levels of several ceramide species were increased while levels of sphingomyelin were decreased
We quantified the amount of total SMase in the peripheral plasma of myeloma patient samples
Summary
Multiple myeloma (MM) is a plasma cell malignancy in which the tumoral cells reside in the bone marrow. As such, it is one of the most common hematological malignancies, second only to non-Hodgkin lymphomas. MM is notorious for its drug resistance, due to both extrinsic mechanisms through interaction with the bone marrow microenvironment, as well as intrinsic adaptations of the myeloma cells themselves [2]. The lipid metabolism has become a more closely studied topic in the field of cancer [3]. Besides being the building blocks of cell membranes or energetic fuel, lipids are known to serve as signaling molecules and are an integral part of cell metabolism
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