sphingosine-kinase and Skin-Neoplasms

Topics: Apoptosis; Carcinoma, Squamous Cell; Cell Line, Tumor; Cell Survival; Humans; MicroRNAs; Phosphotransferases (Alcohol Group Acceptor); Skin Neoplasms

Immune checkpoint inhibitors (ICIs) have dramatically modified the prognosis of several advanced cancers, however many patients still do not respond to treatment. Optimal results might be obtained by targeting cancer cell metabolism to modulate the immunosuppressive tumor microenvironment. Here, we identify sphingosine kinase-1 (SK1) as a key regulator of anti-tumor immunity. Increased expression of SK1 in tumor cells is significantly associated with shorter survival in metastatic melanoma patients treated with anti-PD-1. Targeting SK1 markedly enhances the responses to ICI in murine models of melanoma, breast and colon cancer. Mechanistically, SK1 silencing decreases the expression of various immunosuppressive factors in the tumor microenvironment to limit regulatory T cell (Treg) infiltration. Accordingly, a SK1-dependent immunosuppressive signature is also observed in human melanoma biopsies. Altogether, this study identifies SK1 as a checkpoint lipid kinase that could be targeted to enhance immunotherapy.

Topics: Aged; Animals; Antibodies, Monoclonal, Humanized; Antineoplastic Agents, Immunological; CD8-Positive T-Lymphocytes; Drug Resistance, Neoplasm; Female; Gene Expression Regulation, Enzymologic; Gene Expression Regulation, Neoplastic; Humans; Male; Melanoma; Melanoma, Experimental; Mice, Inbred BALB C; Middle Aged; Molecular Targeted Therapy; Nivolumab; Phosphotransferases (Alcohol Group Acceptor); Programmed Cell Death 1 Receptor; Skin Neoplasms; Survival Rate; T-Lymphocytes, Regulatory; Tumor Escape

In this issue of Oncogene, Albinet et al. have demonstrated a critical role of melanoma sphingosine kinase 1, which catalyses formation of sphingosine 1-phosphate (S1P), in promoting the differentiation of fibroblasts into myofibroblasts. The myofibroblast sphingosine kinase 1 then promotes the S1P-dependent dissemination (metastasis) of melanoma cells via a S1P receptor 3-mediated mechanism. These findings are of major significance because they provide a novel mechanism of interaction between melanoma and the microenvironment niche in promoting metastasis. These studies therefore identify S1P derived from myofibroblasts and melanoma cells as a novel target for therapeutic intervention.

Topics: Animals; Female; Fibroblasts; Humans; Melanoma; Phosphotransferases (Alcohol Group Acceptor); Skin Neoplasms

Despite progress in the understanding of the biology and genetics of melanoma, no effective treatment against this cancer is available. The adjacent microenvironment has an important role in melanoma progression. Defining the molecular signals that control the bidirectional dialog between malignant cells and the surrounding stroma is crucial for efficient targeted therapy. Our study aimed at defining the role of sphingosine-1-phosphate (S1P) in melanoma-stroma interactions. Transcriptomic analysis of human melanoma cell lines showed increased expression of sphingosine kinase-1 (SPHK1), the enzyme that produces S1P, as compared with normal melanocytes. Such an increase was also observed by immunohistochemistry in melanoma specimens as compared with nevi, and occurred downstream of ERK activation because of BRAF or NRAS mutations. Importantly, migration of melanoma cells was not affected by changes in SPHK1 activity in tumor cells, but was stimulated by comparable modifications of S1P-metabolizing enzymes in cocultured dermal fibroblasts. Reciprocally, incubation of fibroblasts with the conditioned medium from SPHK1-expressing melanoma cells resulted in their differentiation to myofibroblasts, increased production of matrix metalloproteinases and enhanced SPHK1 expression and activity. In vivo tumorigenesis experiments showed that the lack of S1P in the microenvironment prevented the development of orthotopically injected melanoma cells. Finally, local tumor growth and dissemination were enhanced more efficiently by coinjection of wild-type skin fibroblasts than by fibroblasts from Sphk1(-/-) mice. This report is the first to document that SPHK1/S1P modulates the communication between melanoma cells and dermal fibroblasts. Altogether, our findings highlight SPHK1 as a potential therapeutic target in melanoma progression.

Topics: Aldehyde-Lyases; Animals; Cell Communication; Cell Differentiation; Cell Movement; Cell Transformation, Neoplastic; Extracellular Signal-Regulated MAP Kinases; Female; Fibroblasts; Gene Expression Profiling; GTP Phosphohydrolases; HEK293 Cells; Humans; Lysophospholipids; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Melanoma; Membrane Proteins; Mice; Mice, Inbred C57BL; Mice, Knockout; Myofibroblasts; Phosphotransferases (Alcohol Group Acceptor); Proto-Oncogene Proteins B-raf; RNA Interference; RNA, Messenger; RNA, Small Interfering; Skin Neoplasms; Sphingosine

Resistance to therapies develops rapidly for melanoma leading to more aggressive disease. Therefore, agents are needed that specifically inhibit proteins or pathways controlling the development of this disease, which can be combined, dependent on genes deregulated in a particular patient's tumors. This study shows that elevated sphingosine-1-phosphate (S-1-P) levels resulting from increased activity of sphingosine kinase-1 (SPHK1) occur in advanced melanomas. Targeting SPHK1 using siRNA decreased anchorage-dependent and -independent growth as well as sensitized melanoma cells to apoptosis-inducing agents. Pharmacological SPHK1 inhibitors SKI-I but not SKI-II decreased S-1-P content, elevated ceramide levels, caused a G2-M block and induced apoptotic cell death in melanomas. Targeting SPHK1 using siRNA or the pharmacological agent called SKI-I decreased the levels of pAKT. Furthermore, SKI-I inhibited the expression of CYCLIN D1 protein and increased the activity of caspase-3/7, which in turn led to the degradation of PARP. In animals, SKI-I but not SKI-II retarded melanoma growth by 25-40%. Thus, targeting SPHK1 using siRNAs or SKI-I has therapeutic potential for melanoma treatment either alone or in combination with other targeted agents.

Topics: Animals; Apoptosis; Cell Adhesion; Cell Line, Tumor; Cell Proliferation; Cell Survival; Cyclin D1; Down-Regulation; Fibroblasts; G1 Phase Cell Cycle Checkpoints; Humans; Lysophospholipids; Melanocytes; Melanoma; Mice; Molecular Targeted Therapy; Phosphotransferases (Alcohol Group Acceptor); Protein Kinase Inhibitors; Proto-Oncogene Proteins c-akt; Resting Phase, Cell Cycle; RNA, Small Interfering; Skin Neoplasms; Sphingosine; Staurosporine; Thiazoles; Up-Regulation; Xenograft Model Antitumor Assays

In melanoma, the activation of pro-survival signaling pathways, such as the AKT and NF-κB pathways, is critical for tumor growth. We have recently reported that the AKT inhibitor BI-69A11 causes efficient inhibition of melanoma growth. Here, we show that in addition to its AKT inhibitory activity, BI-69A11 also targets the NF-κB pathway. In melanoma cell lines, BI-69A11 inhibited TNF-α-stimulated IKKα/β and IκB phosphorylation as well as NF-κB reporter gene expression. Furthermore, the effective inhibition of melanoma growth by BI-69A11 was attenuated upon NF-κB activation. Mechanistically, reduced NF-κB signaling by BI-69-A11 is mediated by the inhibition of sphingosine kinase 1, identified in a screen of 315 kinases. Significantly, we demonstrate that BI-69A11 is well tolerated and orally active against UACC 903 and SW1 melanoma xenografts. Our results demonstrate that BI-69A11 inhibits both the AKT and the NF-κB pathways and that the dual targeting of these pathways may be efficacious as a therapeutic strategy in melanoma.

Topics: Administration, Oral; Animals; Benzimidazoles; Cell Line, Tumor; Cell Proliferation; Drug Resistance, Neoplasm; Humans; Melanoma; Mice; Mice, Nude; Molecular Targeted Therapy; NF-kappa B; Phosphotransferases (Alcohol Group Acceptor); Proto-Oncogene Proteins B-raf; Proto-Oncogene Proteins c-akt; Quinolones; Signal Transduction; Skin Neoplasms; Xenograft Model Antitumor Assays