Systematic classification of melanoma cells by phenotype‐specific gene expression mapping

Widmer, Daniel; Cheng, Phil F.; Eichhoff, Ossia M.; Belloni, Benedetta; Zipser, Marie; Schlegel, Natalie C.; Javelaud, Delphine; Mauviel, Alain; Dummer, Reinhard; Hoek, Keith S.

doi:10.1111/j.1755-148x.2012.00986.x

Cited by 170 publications

(254 citation statements)

References 49 publications

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“…9 and supplemental Table S1), as shown previously for other AC inhibitors of the same class on colon cancer cells (12). Experiments in G361 cells, a melanoma cell line with a proliferative phenotype (25), showed that ARN14988 acted synergistically with 5-fluorouracil (Fig. 9, A and C).…”

Section: High Ac Expression In Human Melanoma Cell Lines Andsupporting

confidence: 79%

“…The phenotype-switching model is an innovative model of tumor progression to describe cancer development, metastasis, and resistance to therapy (25,(43)(44)(45)(46)(47). This model posits that melanoma cells can switch between two states: cells with high proliferative potential, which are less invasive, and cells with high metastatic potential, which are less proliferative.…”

Section: Discussionmentioning

confidence: 99%

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Acid Ceramidase in Melanoma

Realini

Palese

Pizzirani

et al. 2016

Journal of Biological Chemistry

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Acid ceramidase (AC) is a lysosomal cysteine amidase that controls sphingolipid signaling by lowering the levels of ceramides and concomitantly increasing those of sphingosine and its bioactive metabolite, sphingosine 1-phosphate. In the present study, we evaluated the role of AC-regulated sphingolipid signaling in melanoma. We found that AC expression is markedly elevated in normal human melanocytes and proliferative melanoma cell lines, compared with other skin cells (keratinocytes and fibroblasts) and non-melanoma cancer cells. High AC expression was also observed in biopsies from human subjects with Stage II melanoma. Immunofluorescence studies revealed that the subcellular localization of AC differs between melanocytes (where it is found in both cytosol and nucleus) and melanoma cells (where it is primarily localized to cytosol). In addition to having high AC levels, melanoma cells generate lower amounts of ceramides than normal melanocytes do. This downregulation in ceramide production appears to result from suppression of the de novo biosynthesis pathway. To test whether AC might contribute to melanoma cell proliferation, we blocked AC activity using a new potent (IC 50 ‫؍‬ 12 nM) and stable inhibitor. AC inhibition increased cellular ceramide levels, decreased sphingosine 1-phosphate levels, and acted synergistically with several, albeit not all, antitumoral agents. The results suggest that AC-controlled sphingolipid metabolism may play an important role in the control of melanoma proliferation.Ceramides are a class of bioactive lipids that regulate senescence, apoptosis, and autophagy (1). They comprise more than 200 chemically and functionally distinct molecules and are produced through either de novo biosynthesis or cleavage of preformed sphingolipid precursors in membranes (2-4). They are degraded by the action of five distinct ceramidases, which differ in sequence, structure, subcellular localization, and preferred substrates (5). Among them, acid ceramidase (AC) 2 (also known as N-acetylsphingosine amidohydrolase, ASAH1) is especially relevant due to its possible roles in cancer progression and chemoresistance (6). AC is a lysosomal cysteine amidase that catalyzes the hydrolysis of ceramide into sphingosine and fatty acid with a preference for unsaturated ceramides with 6 -16-carbon acyl chains (5). Its activation is associated with decreased cellular levels of these medium-chain ceramides, which promote senescence and apoptosis, and increased levels of sphingosine 1-phosphate (S1P), which stimulates cell proliferation and cancer cell migration (7). A bioinformatic survey of the National Cancer Institute (NCI) gene expression database conducted in 2003 identified AC as a potential candidate for the development of new biomarkers for the prognosis of melanoma (8). Supporting this possibility, subsequent studies showed that serum of melanoma patients contains AC autoantibodies (9). Moreover, experiments with melanoma cell lines in cultures have demonstrated that dacarbazine, a standard of care for the...

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Section: High Ac Expression In Human Melanoma Cell Lines Andsupporting

confidence: 79%

Section: Discussionmentioning

confidence: 99%

Acid Ceramidase in Melanoma

Realini

Palese

Pizzirani

et al. 2016

Journal of Biological Chemistry

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“…broadinstitute.org/gsea/msigdb) were considered enriched at a significance level of FDR ≤0.05. Additionally, proliferative and invasive gene signatures (Widmer et al 2012) were included in GSEAs to test for enrichment. The DE signature was used to score expression profiles of individual samples in the Zurich, Philadelphia, and Mannheim data sets as well as profiles of individual TCGA tumors in skin cutaneous melanoma, breastinvasive carcinoma, lung adenocarcinoma, and colon adenocarcinoma data sets using single-sample GSEA (ssGSEA).…”

Section: Gene Expression and Bioinformatics Analysesmentioning

confidence: 99%

BMI1 induces an invasive signature in melanoma that promotes metastasis and chemoresistance

et al. 2015

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Melanoma can switch between proliferative and invasive states, which have identifying gene expression signatures that correlate with good and poor prognosis, respectively. However, the mechanisms controlling these signatures are poorly understood. In this study, we identify BMI1 as a key determinant of melanoma metastasis by which its overexpression enhanced and its deletion impaired dissemination. Remarkably, in this tumor type, BMI1 had no effect on proliferation or primary tumor growth but enhanced every step of the metastatic cascade. Consistent with the broad spectrum of effects, BMI1 activated widespread gene expression changes, which are characteristic of melanoma progression and also chemoresistance. Accordingly, we showed that up-regulation or down-regulation of BMI1 induced resistance or sensitivity to BRAF inhibitor treatment and that induction of noncanonical Wnt by BMI1 is required for this resistance. Finally, we showed that our BMI1-induced gene signature encompasses all of the hallmarks of the previously described melanoma invasive signature. Moreover, our signature is predictive of poor prognosis in human melanoma and is able to identify primary tumors that are likely to become metastatic. These data yield key insights into melanoma biology and establish BMI1 as a compelling drug target whose inhibition would suppress both metastasis and chemoresistance of melanoma.

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“…Recently, expression of CXCR7 was found through candidate gene RT-PCR and RNAseq analysis in human melanoma cell lines (52,53), as well as medaka aquarium fish melanomas (54) and normal melanocytes (55). Furthermore, CXCR7 is necessary for melanocyte and medaka melanoma SDF1-dependent migration (54,55).…”

Section: Discussionmentioning

confidence: 99%

PAX3 and FOXD3 Promote CXCR4 Expression in Melanoma

Kubic

Lui

Little

et al. 2015

Journal of Biological Chemistry

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Background: CXCR4 promotes melanoma metastasis. Results: FOXD3 and PAX3 drive CXCR4 expression. Blocking these factors inhibits cell migration, but this is rescued by ectopic CXCR4 expression. Conclusion: PAX3-and FOXD3-mediated melanoma cell migration is dependent on promoting the expression of CXCR4. Significance: This study identifies a new pathway and targets for therapeutic strategies to treat invasive melanoma.

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Systematic classification of melanoma cells by phenotype‐specific gene expression mapping

Cited by 170 publications

References 49 publications

Acid Ceramidase in Melanoma

Acid Ceramidase in Melanoma

BMI1 induces an invasive signature in melanoma that promotes metastasis and chemoresistance

PAX3 and FOXD3 Promote CXCR4 Expression in Melanoma

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