Molecular subtyping of metastatic melanoma based on cell ganglioside metabolism profiles

Tringali, Cristina; Silvestri, Ilaria; Testa, Francesca; Baldassari, Paola; Anastasia, Luigi; Mortarini, Roberta; Anichini, Andrea; López‐Requena, Alejandro; Tettamanti, Guido; Venerando, Bruno

doi:10.1186/1471-2407-14-560

Cited by 33 publications

(33 citation statements)

References 60 publications

(73 reference statements)

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“…This lysosomal enzyme is involved in hydrolysis of gangliosides GM2 to GM3. A recent study by Tringali et al showed that poor survival in melanoma is significantly related to GM3 levels [47]. These data agree well with our preliminary finding of elevated HEXB levels in patients with poor survival.…”

Section: Resultssupporting

confidence: 92%

Correlation of histopathologic characteristics to protein expression and function in malignant melanoma

et al. 2017

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BackgroundMetastatic melanoma is still one of the most prevalent skin cancers, which upon progression has neither a prognostic marker nor a specific and lasting treatment. Proteomic analysis is a versatile approach with high throughput data and results that can be used for characterizing tissue samples. However, such analysis is hampered by the complexity of the disease, heterogeneity of patients, tumors, and samples themselves. With the long term aim of quest for better diagnostics biomarkers, as well as predictive and prognostic markers, we focused on relating high resolution proteomics data to careful histopathological evaluation of the tumor samples and patient survival information.Patients and methodsRegional lymph node metastases obtained from ten patients with metastatic melanoma (stage III) were analyzed by histopathology and proteomics using mass spectrometry. Out of the ten patients, six had clinical follow-up data. The protein deep mining mass spectrometry data was related to the histopathology tumor tissue sections adjacent to the area used for deep-mining. Clinical follow-up data provided information on disease progression which could be linked to protein expression aiming to identify tissue-based specific protein markers for metastatic melanoma and prognostic factors for prediction of progression of stage III disease.ResultsIn this feasibility study, several proteins were identified that positively correlated to tumor tissue content including IF6, ARF4, MUC18, UBC12, CSPG4, PCNA, PMEL and MAGD2. The study also identified MYC, HNF4A and TGFB1 as top upstream regulators correlating to tumor tissue content. Other proteins were inversely correlated to tumor tissue content, the most significant being; TENX, EHD2, ZA2G, AOC3, FETUA and THRB. A number of proteins were significantly related to clinical outcome, among these, HEXB, PKM and GPNMB stood out, as hallmarks of processes involved in progression from stage III to stage IV disease and poor survival.ConclusionIn this feasibility study, promising results show the feasibility of relating proteomics to histopathology and clinical outcome, and insight thus can be gained into the molecular processes driving the disease. The combined analysis of histological features including the sample cellular composition with protein expression of each metastasis enabled the identification of novel, differentially expressed proteins. Further studies are necessary to determine whether these putative biomarkers can be utilized in diagnostics and prognostic prediction of metastatic melanoma.

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Section: Resultssupporting

confidence: 92%

Correlation of histopathologic characteristics to protein expression and function in malignant melanoma

et al. 2017

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“…It has been suggested that hypoxic culture induces the expression of sialin, a sialic acid transporter, leading to increased incorporation of NeuGc from the external environment [9]. Indeed, a recent study of aggressive melanoma showed that the amount of NeuGc GM3 depended on the external medium [24]. However, we did not observe an increased expression of NeuGc GM3 using media supplemented with fetal bovine serum, which contains NeuGc ( Figure S2).…”

Section: Resultscontrasting

confidence: 49%

“…It is present on the surface of multiple types of cancers, such as breast cancer [19], melanoma [20], lung cancer [21] and retinoblastoma [22]. NeuGc GM3 not only has promising therapeutic and diagnostic potential but also holds a prognostic value, since its expression correlates with more aggressive disease [21,23,24]. Hypoxia has been recognized as an important and common characteristic of many advanced tumors, where progression occurs as a result of adaptation to and survival within the environment limited in oxygen [25].…”

Section: Introductionmentioning

confidence: 99%

“…In addition, hypoxia-induced cancer progression can affect the expression of cell surface antigens, and indeed, the expression of NeuGc gangliosides has been shown to be triggered by hypoxic condition [9]. Moreover, the aggressiveness of tumors correlates with CMAH expression levels [24], whereas in the brain, which is rich in oxygen, CMAH gene and NeuGc expression are suppressed [26]. However, the cellular mechanism causing the hypoxia-induced expression of NeuGc GM3 is still unknown.…”

Section: Introductionmentioning

confidence: 99%

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Hypothesis: Hypoxia inducesde novosynthesis of NeuGc gangliosides in humans through CMAH domain substitute

Bousquet

Sandvig

Edin

et al. 2017

Preprint

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Immunotherapy is a growing field in cancer research. A privileged tumor-associated antigen that has received much attention is N-glycolyl (NeuGc) GM3. This ganglioside is present in several types of cancer, but is almost undetectable in human healthy tissues. However, its non-hydroxylated variant, NeuAc GM3, is abundant in all mammals. Due to a deletion in the human gene encoding the key enzyme for synthesis of NeuGc, humans, in contrast to other mammals, cannot synthesize NeuGc GM3. Therefore the presence of this ganglioside in human cancer cells represents an enigma. It has been shown that hypoxic conditions trigger the expression of NeuGc gangliosides, which not only serve as attractive targets for cancer therapy, but also as diagnostic and prognostic tumor marker. Here, we confirm hypoxia-induced expression of the NeuGc GM3 ganglioside also in HeLa cells and reveal several candidate proteins, in particular GM3 synthase and subunit B of respiratory complex II (SDHB), that may be involved in the generation of NeuGc GM3 by SILAC-based proteome analysis. These findings have the potential to significantly advance our understanding of how this enigmatic tumor-associated antigen is produced in humans, and also suggest a possible mechanism of action of anti-tumor antibodies that recognize hypoxia markers, such as 14F7.

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“…Membrane Neu3 is also highly expressed in human melanoma cells where it promotes cell growth with minimal changes in the composition of gangliosides [140]. Moreover, other studies have reported a relationship between NEU3 and GD3 synthase genes that were significantly up-regulated in melanomas in comparison to melanocytes, possibly as a direct consequence of the increased expression of the transcriptional factor Sp1 [141]. Neu3 could be involved in melanoma malignancy by decreasing the levels of Neu5Ac-GM3.…”

Section: Aberrant Sialylation In Cancer Progression and Metastasismentioning

confidence: 99%

Neuraminidase-1: A novel therapeutic target in multistage tumorigenesis

2016

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Several of the growth factors and their receptor tyrosine kinases (RTK) such as epidermal growth factor (EGF), platelet-derived growth factor (PDGF), fibroblast growth factor (FGF), vascular endothelial growth factor (VEGF), nerve growth factor (NGF) and insulin are promising candidate targets for cancer therapy. Indeed, tyrosine kinase inhibitors (TKI) have been developed to target these growth factors and their receptors, and have demonstrated dramatic initial responses in cancer therapy. Yet, most patients ultimately develop TKI drug resistance and relapse. It is essential in the clinical setting that the targeted therapies are to circumvent multistage tumorigenesis, including genetic mutations at the different growth factor receptors, tumor neovascularization, chemoresistance of tumors, immune-mediated tumorigenesis and the development of tissue invasion and metastasis. Here, we identify a novel receptor signaling platform linked to EGF, NGF, insulin and TOLL-like receptor (TLR) activations, all of which are known to play major roles in tumorigenesis. The importance of these findings signify an innovative and promising entirely new targeted therapy for cancer. The role of mammalian neuraminidase-1 (Neu1) in complex with matrix metalloproteinase-9 and G protein-coupled receptor tethered to RTKs and TLRs is identified as a major target in multistage tumorigenesis. Evidence exposing the link connecting growth factor-binding and immune-mediated tumorigenesis to this novel receptor-signaling paradigm will be reviewed in its current relationship to cancer.

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Molecular subtyping of metastatic melanoma based on cell ganglioside metabolism profiles

Cited by 33 publications

References 60 publications

Correlation of histopathologic characteristics to protein expression and function in malignant melanoma

Correlation of histopathologic characteristics to protein expression and function in malignant melanoma

Hypothesis: Hypoxia inducesde novosynthesis of NeuGc gangliosides in humans through CMAH domain substitute

Neuraminidase-1: A novel therapeutic target in multistage tumorigenesis

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