Alterations in Plasma Lipid Profiles Associated with Melanoma and Therapy Resistance

Abstract

Dysfunctions of lipid metabolism are associated with tumor progression and treatment resistance of cutaneous melanoma. BRAF/MEK inhibitor resistance is linked to alterations of melanoma lipid pathways. We evaluated whether a specific lipid pattern characterizes plasma from melanoma patients and their response to therapy. Plasma samples from patients and controls were analyzed for FASN and DHCR24 levels and lipidomic profiles. FASN and DHCR24 expression resulted in association with disease condition and related to plasma cholesterol and triglycerides in patients at different disease stages (n = 144) as compared to controls (n = 115). Untargeted lipidomics in plasma (n = 40) from advanced disease patients and controls revealed altered levels of different lipids, including fatty acid derivatives and sphingolipids. Targeted lipidomics identified higher levels of dihydroceramides, ceramides, sphingomyelins, ganglioside GM3, sphingosine, sphingosine-1-phosphate, and dihydrosphingosine, saturated and unsaturated fatty acids. When melanoma patients were stratified based on a long/short-term clinical response to kinase inhibitors, differences in plasma levels were shown for saturated fatty acids (FA 16:0, FA18:0) and oleic acid (FA18:1). Our results associated altered levels of selected lipid species in plasma of melanoma patients with a more favorable prognosis. Although obtained in a small cohort, these results pave the way to lipidomic profiling for melanoma patient stratification.

Elucidating the Role of Lipid-Metabolism-Related Signal Transduction and Inhibitors in Skin Cancer

“…The phosphatidylinositol 3-kinase (PI3K)/AKT and mammalian target of rapamycin (mTOR) signaling pathways, which are often activated in melanoma, play a crucial role in conferring resistance to targeted therapy, immunotherapy, and chemotherapy [ 28 , 29 , 30 , 31 ]. PI3Ks, a unique and conserved group of intracellular lipid kinases, phosphorylate the 3′-hydroxyl group on phosphatidylinositol [ 32 ].…”

“…Dei Cas et al reported an association between resistance to B-Raf/MEK inhibitors in melanoma and alterations in lipid pathways. They observed that that expression levels of FASN and seladin-1/24-dehydrocholesterol reductase (DHCR24) are correlated with the disease state, which is linked to differences in plasma cholesterol and triglyceride levels between patients and control subjects [ 31 ]. Lipidomic analysis revealed elevated levels of dihydroceramides, ceramides, sphingosine, sphingosine-1-phosphate, dihydrosphingosine, sphingomyelins, ganglioside GM3, and a range of both saturated and unsaturated fatty acids [ 31 ].…”

“…They observed that that expression levels of FASN and seladin-1/24-dehydrocholesterol reductase (DHCR24) are correlated with the disease state, which is linked to differences in plasma cholesterol and triglyceride levels between patients and control subjects [ 31 ]. Lipidomic analysis revealed elevated levels of dihydroceramides, ceramides, sphingosine, sphingosine-1-phosphate, dihydrosphingosine, sphingomyelins, ganglioside GM3, and a range of both saturated and unsaturated fatty acids [ 31 ]. DHCR24 is expressed at higher levels in melanoma metastases compared to primary tumors, and its elevated expression is associated with resistance to apoptosis [ 52 ].…”