New Insights into the Role of Sphingolipid Metabolism in Melanoma

Abstract

Cutaneous melanoma is a deadly skin cancer whose aggressiveness is directly linked to its metastatic potency. Despite remarkable breakthroughs in term of treatments with the emergence of targeted therapy and immunotherapy, the prognosis for metastatic patients remains uncertain mainly because of resistances. Better understanding the mechanisms responsible for melanoma progression is therefore essential to uncover new therapeutic targets. Interestingly, the sphingolipid metabolism is dysregulated in melanoma and is associated with melanoma progression and resistance to treatment. This review summarises the impact of the sphingolipid metabolism on melanoma from the initiation to metastatic dissemination with emphasis on melanoma plasticity, immune responses and resistance to treatments.

The Role of Ceramide Metabolism and Signaling in the Regulation of Mitophagy and Cancer Therapy

“…In melanoma cells, knockdown of SphK1 inhibited the secretion of immunosuppressive cytokines (ex. TGF-β), which sensitized the melanoma cells to anti-PD-1 and anti-CTLA-4 immunotherapies in mice [180][181][182]. S1P secretion from lung cancer cells was also found to impair CD8 positive T cell responses, facilitating metastasis [180].…”

“…TGF-β), which sensitized the melanoma cells to anti-PD-1 and anti-CTLA-4 immunotherapies in mice [180][181][182]. S1P secretion from lung cancer cells was also found to impair CD8 positive T cell responses, facilitating metastasis [180]. Patients with bladder cancer were found to have higher levels of S1PR1 and immunosuppressive cytokine secretion (TGF-β, IL-10), along with more circulating and tumor-infiltrating regulatory T cells, which is associated with poor patient outcomes [183].…”

Targeted Metabolomics Identifies Plasma Biomarkers in Mice with Metabolically Heterogeneous Melanoma Xenografts

“…Cer have been reported to be involved in differentiation, proliferation, growth arrest, and apoptosis [ 67 ]. Several studies have showed that melanoma cells are able to rearrange sphingolipid metabolism by preventing intracellular Cer accumulation by induction of Cer-degrading enzymes and downregulation of Cer-promoting enzymes [ 68 ]. Thus, increasing the intracellular levels of Cer was shown to reduce cancer cell proliferation [ 69 , 70 , 71 , 72 , 73 , 74 , 75 ].…”

Cholesterol and Sphingolipid Enriched Lipid Rafts as Therapeutic Targets in Cancer

“…Many studies have suggested that the SphK1/S1P axis could play a role in the promotion of several types of tumors, based on the overexpression of SphK1 in tumor cell lines and in patient samples, and sometimes, on the measured increased S1P levels in tumors and/or in patient blood. These studies have recently been reviewed for breast [ 46 ], ovarian, [ 47 ], and gastrointestinal cancers [ 48 ], hepatocellular carcinoma [ 49 ], melanoma [ 50 ] and glioblastoma [ 51 ]. High S1P in breast tumor tissue is significantly associated with lymphnode metastasis [ 52 ].…”