Proteomics analysis of melanoma metastases: association between S100A13 expression and chemotherapy resistance.
BACKGROUND
Disseminated cutaneous malignant melanoma (CMM) is commonly unresponsive to standard chemotherapies, and there are as yet no predictive markers of therapy response.


METHODS
In the present study we collected fresh-frozen pretreatment lymph-node metastasis samples (n=14) from melanoma patients with differential response to dacarbazine (DTIC) or temozolomide (TMZ) chemotherapy, to identify proteins with an impact on treatment response. We performed quantitative protein profiling using tandem mass spectrometry and compared the proteome differences between responders (R) and non-responders (NR), matched for age, gender and histopathological type of CMM.


RESULTS
Biological pathway analyses showed several signalling pathways differing between R vs NR, including Rho signalling. Gene expression profiling data was available for a subset of the samples, and the results were compared with the proteomics data. Four proteins with differential expression between R and NR were selected for technical validation by immunoblotting (ISYNA1, F13A1, CSTB and S100A13), and CSTB and S100A13 were further validated on a larger sample set by immunohistochemistry (n=48). The calcium binding protein S100A13 was found to be significantly overexpressed in NR compared with R in all analyses performed.


CONCLUSIONS
Our results suggest that S100A13 is involved in CMM resistance to DTIC/TMZ.
Department of Oncology-Pathology, Karolinska Institutet, CCK R8:03, Karolinska University Hospital, Solna, S-17176 Stockholm, Sweden.
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Azimi
Department of Oncology-Pathology, Karolinska Institutet, Science for Life Laboratory, Tomtebodavägen 23, S-17165 Solna, Sweden.
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Pernemalm
Department of Oncology-Pathology, Karolinska Institutet, CCK R8:03, Karolinska University Hospital, Solna, S-17176 Stockholm, Sweden.
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Frostvik Stolt
Department of Oncology-Pathology, Karolinska Institutet, CCK R8:03, Karolinska University Hospital, Solna, S-17176 Stockholm, Sweden.
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Hansson
Department of Oncology-Pathology, Karolinska Institutet, Science for Life Laboratory, Tomtebodavägen 23, S-17165 Solna, Sweden.
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Lehtiö
Department of Oncology-Pathology, Karolinska Institutet, CCK R8:03, Karolinska University Hospital, Solna, S-17176 Stockholm, Sweden.
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Egyházi Brage
Department of Oncology-Pathology, Karolinska Institutet, CCK R8:03, Karolinska University Hospital, Solna, S-17176 Stockholm, Sweden.
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Hertzman Johansson
D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D055313:Cystatin B / Q000096:biosynthesis / Q000235:genetics; D003606:Dacarbazine / Q000031:analogs & derivatives* / Q000494:pharmacology* / Q000627:therapeutic use; D019008:Drug Resistance, Neoplasm / Q000502:physiology*; D005176:Factor XIII / Q000096:biosynthesis / Q000235:genetics; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D008207:Lymphatic Metastasis; D008297:Male; D008545:Melanoma / Q000188:drug therapy / Q000378:metabolism / Q000556:secondary*; D008875:Middle Aged; D007296:Myo-Inositol-1-Phosphate Synthase / Q000096:biosynthesis / Q000235:genetics; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D011446:Prospective Studies; D040901:Proteomics / Q000379:methods*; D009418:S100 Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000473:pathology; D053719:Tandem Mass Spectrometry; D000077204:Temozolomide; D055815:Young Adult; D000096142:Cutaneous Malignant Melanoma
D000970:Antineoplastic Agents; C524994:CSTB protein, human; D009363:Neoplasm Proteins; D009418:S100 Proteins; C511523:S100A13 protein, human; C064015:factor XIII subunit A; D003606:Dacarbazine; D055313:Cystatin B; D005176:Factor XIII; D007296:Myo-Inositol-1-Phosphate Synthase; D000077204:Temozolomide