{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,12]],"date-time":"2025-10-12T03:21:50Z","timestamp":1760239310069,"version":"build-2065373602"},"reference-count":47,"publisher":"MDPI AG","issue":"21","license":[{"start":{"date-parts":[[2020,10,31]],"date-time":"2020-10-31T00:00:00Z","timestamp":1604102400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100013129","name":"against breast cancer","doi-asserted-by":"publisher","award":["ABCD01"],"award-info":[{"award-number":["ABCD01"]}],"id":[{"id":"10.13039\/100013129","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100011726","name":"Wessex Medical Research","doi-asserted-by":"publisher","award":["WMR"],"award-info":[{"award-number":["WMR"]}],"id":[{"id":"10.13039\/100011726","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Formalin-fixed paraffin embedded (FFPE) clinical tissues represent an abundant and unique resource for translational proteomic studies. In the US, melanoma is the 5th and 6th most common cancer in men and women, respectively, affecting over 230,000 people annually and metastasising in 5\u201315% of cases. Median survival time for distant metastatic melanoma is 6\u20139 months with a 5-year-survival of &lt; 15%. In this study, 24 primary FFPE tumours which have metastasised (P-M) and 24 primary FFPE tumours which did not metastasise (P-NM) were subjected to proteomic profiling. In total, 2750 proteins were identified, of which 16 were significantly differentially expressed. Analysis of TCGA data demonstrated that expression of the genes encoding for 6 of these 16 proteins had a significant effect on survival in cutaneous melanoma. Pathway analysis of the proteomics data revealed mechanisms likely involved in the process of melanoma metastasis, including cytoskeleton rearrangement, extracellular changes and immune system alterations. A machine learning prediction model scoring an AUC of 0.922, based on these 16 differentially expressed proteins was able to accurately classify samples into P-M and P-NM. This study has identified potential biomarkers and key processes relating to melanoma metastasis using archived clinical samples, providing a basis for future studies in larger cohorts.<\/jats:p>","DOI":"10.3390\/ijms21218160","type":"journal-article","created":{"date-parts":[[2020,10,31]],"date-time":"2020-10-31T21:39:56Z","timestamp":1604180396000},"page":"8160","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Proteomic Profiling of Archived Tissue of Primary Melanoma Identifies Proteins Associated with Metastasis"],"prefix":"10.3390","volume":"21","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4147-6956","authenticated-orcid":false,"given":"Andrew","family":"Shapanis","sequence":"first","affiliation":[{"name":"Centre for Proteomic Research, Biological Sciences, University of Southampton, Southampton SO17 1BJ, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2282-5655","authenticated-orcid":false,"given":"Chester","family":"Lai","sequence":"additional","affiliation":[{"name":"Dermatopharmacology, Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton SO16 6YD, UK"},{"name":"Dermatology, University Hospital Southampton NHS Foundation Trust, Southampton SO16 6YD, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mathew","family":"Sommerlad","sequence":"additional","affiliation":[{"name":"Histopathology, University Hospital Southampton NHS Foundation Trust, Southampton SO16 6YD, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Erika","family":"Parkinson","sequence":"additional","affiliation":[{"name":"Centre for Proteomic Research, Biological Sciences, University of Southampton, Southampton SO17 1BJ, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5591-6970","authenticated-orcid":false,"given":"Eugene","family":"Healy","sequence":"additional","affiliation":[{"name":"Dermatopharmacology, Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton SO16 6YD, UK"},{"name":"Dermatology, University Hospital Southampton NHS Foundation Trust, Southampton SO16 6YD, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2995-2959","authenticated-orcid":false,"given":"Paul","family":"Skipp","sequence":"additional","affiliation":[{"name":"Centre for Proteomic Research, Biological Sciences, University of Southampton, Southampton SO17 1BJ, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2020,10,31]]},"reference":[{"key":"ref_1","first-page":"50589","article-title":"Proteomic sample preparation from formalin fixed and paraffin embedded tissue","volume":"79","author":"Wisniewski","year":"2013","journal-title":"J. Vis. Exp."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"304","DOI":"10.1021\/pr200019m","article-title":"High Recovery Fasp Applied to The Proteomic Analysis of Microdissected Formalin Fixed Paraffin Embedded Cancer Tissues Retrieves Known Colon Cancer Markers","volume":"10","author":"Wisniewski","year":"2011","journal-title":"J. Proteome. Res."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"403","DOI":"10.1002\/mas.21598","article-title":"Proteome Analysis of Tissues by Mass Spectrometry","volume":"38","author":"Dapic","year":"2019","journal-title":"Mass. Spectrom. Rev."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"971","DOI":"10.1016\/S0140-6736(18)31559-9","article-title":"Melanoma","volume":"392","author":"Schadendorf","year":"2018","journal-title":"Lancet"},{"key":"ref_5","unstructured":"GLOBOCAN (2019, September 01). GLOBOCAN 2017. Available online: http:\/\/globocan.iarc.fr\/Default.aspx."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"528","DOI":"10.1097\/01.sla.0000090446.63327.40","article-title":"Thin Melanomas: Predictive Lethal Characteristics from A 30-Year Clinical Experience","volume":"238","author":"Kalady","year":"2003","journal-title":"Ann. Surg."},{"key":"ref_7","first-page":"572","article-title":"Survival Rates of Patients with Metastatic Malignant Melanoma","volume":"7","author":"Sandru","year":"2014","journal-title":"J. Med. Life"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"62","DOI":"10.1046\/j.1365-2133.2002.04867.x","article-title":"Metastatic Pathways and Time Courses in The Orderly Progression of Cutaneous Melanoma","volume":"147","author":"Meier","year":"2002","journal-title":"Br. J. Dermatol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"7","DOI":"10.3322\/caac.21332","article-title":"Cancer Statistics, 2016","volume":"66","author":"Siegel","year":"2016","journal-title":"CA Cancer J Clin."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"816","DOI":"10.1016\/S0140-6736(13)60802-8","article-title":"Cutaneous Melanoma","volume":"383","author":"Eggermont","year":"2014","journal-title":"Lancet"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"3296","DOI":"10.3892\/ol.2016.5101","article-title":"Quantitative Label-Free Mass Spectrometry Analysis of Formalin-Fixed, Paraffin-Embedded Tissue Representing The Invasive Cutaneous Malignant Melanoma Proteome","volume":"12","author":"Dowling","year":"2016","journal-title":"Oncol. Lett."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"933","DOI":"10.1111\/j.1600-0560.2011.01761.x","article-title":"A quantitative proteomic analysis of FFPE melanoma","volume":"38","author":"Byrum","year":"2011","journal-title":"J. Cutan. Pathol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"43","DOI":"10.4172\/jpb.1000260","article-title":"Quantitative Proteomics Identifies Activation of Hallmark Pathways of Cancer in Patient Melanoma","volume":"6","author":"Byrum","year":"2013","journal-title":"J. Proteom. Bioinform."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"2658","DOI":"10.1245\/s10434-016-5196-1","article-title":"Breslow Thickness Measurements of Melanomas Around American Joint Committee on Cancer Staging Cut-Off Points: Imprecision and Terminal Digit Bias Have Important Implications for Staging and Patient Management","volume":"23","author":"Ge","year":"2016","journal-title":"Ann. Surg. Oncol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"902","DOI":"10.1097\/00000658-197011000-00017","article-title":"Thickness, Cross-Sectional Areas and Depth of Invasion in The Prognosis of Cutaneous Melanoma","volume":"172","author":"Breslow","year":"1970","journal-title":"Ann. Surg."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"939","DOI":"10.1007\/s00216-012-6203-4","article-title":"Quantitative Mass Spectrometry in Proteomics: Critical Review Update from 2007 to The Present","volume":"404","author":"Bantscheff","year":"2012","journal-title":"Anal. Bioanal. Chem."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1993","DOI":"10.1021\/pr501138h","article-title":"Review, Evaluation, and Discussion of The Challenges of Missing Value Imputation for Mass Spectrometry-Based Label-Free Global Proteomics","volume":"14","author":"Wiberg","year":"2015","journal-title":"J. Proteome. Res."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"207","DOI":"10.1111\/j.1759-7714.2011.00092.x","article-title":"Screening and Identification of Lung Cancer Metastasis-Related Genes by Suppression Subtractive Hybridization","volume":"3","author":"Liu","year":"2012","journal-title":"Thorac. Cancer"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"4484","DOI":"10.1038\/s41598-019-40826-w","article-title":"Six Novel Immunoglobulin Genes as Biomarkers for Better Prognosis in Triple-Negative Breast Cancer by Gene Co-Expression Network Analysis","volume":"9","author":"Hsu","year":"2019","journal-title":"Sci. Rep."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"3996","DOI":"10.18632\/oncotarget.23583","article-title":"Proteomic Profiling of Antibody-Inducing Immunogens in Tumor Tissue Identifies PSMA1, LAP3, ANXA3, and Maspin as Colon Cancer Markers","volume":"9","author":"Yang","year":"2017","journal-title":"Oncotarget"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"13821","DOI":"10.1007\/s13277-016-5172-1","article-title":"Rab11a Sustains GSK3beta\/Wnt\/Beta-Catenin Signaling to Enhance Cancer Progression in Pancreatic Cancer","volume":"37","author":"Yu","year":"2016","journal-title":"Tumour. Biol. J. Int. Soc. Oncodevelopmental Biol. Med."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"872","DOI":"10.1016\/j.jhep.2010.05.019","article-title":"PEBP1 Downregulation Is Associated to Poor Prognosis in HCC Related to Hepatitis B Infection","volume":"53","author":"Xu","year":"2010","journal-title":"J. Hepatol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1016\/j.tranon.2017.11.001","article-title":"eEF1A1 Overexpression Enhances Tumor Progression and Indicates Poor Prognosis in Hepatocellular Carcinoma","volume":"11","author":"Chen","year":"2018","journal-title":"Transl. Oncol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"874","DOI":"10.7150\/jca.27635","article-title":"MYH9 Promotes Growth and Metastasis via Activation of MAPK\/AKT Signaling in Colorectal Cancer","volume":"10","author":"Wang","year":"2019","journal-title":"J. Cancer."},{"key":"ref_25","first-page":"1049","article-title":"MYH9 Overexpression Correlates with Clinicopathological Parameters and Poor Prognosis of Epithelial Ovarian Cancer","volume":"18","author":"Liu","year":"2019","journal-title":"Oncol. Lett."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Fukuda, K., Sugihara, E., Ohta, S., Izuhara, K., Funakoshi, T., Amagai, M., and Saya, S. (2015). Periostin Is a Key Niche Component for Wound Metastasis of Melanoma. PLoS ONE., 10.","DOI":"10.1371\/journal.pone.0129704"},{"key":"ref_27","first-page":"766","article-title":"Effects of Periostin on Hepatocellular Carcinoma Cells Invasion, Metastasis and Prognosis","volume":"27","author":"Wen","year":"2019","journal-title":"Chin. J. Hepatol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"484","DOI":"10.1002\/path.4747","article-title":"Periostin Promotes Immunosuppressive Premetastatic Niche Formation to Facilitate Breast Tumour Metastasis","volume":"239","author":"Wang","year":"2016","journal-title":"J. Pathol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1275","DOI":"10.1158\/0008-5472.CAN-14-2387","article-title":"SND1 Acts Downstream of TGFbeta1 and Upstream of Smurf1 to Promote Breast Cancer Metastasis","volume":"75","author":"Yu","year":"2015","journal-title":"Cancer Res."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"111809","DOI":"10.1016\/j.yexcr.2019.111809","article-title":"SND1 Facilitates The Invasion and Migration of Cervical Cancer Cells by Smurf1-Mediated Degradation of FOXA2","volume":"388","author":"Zhan","year":"2019","journal-title":"Exp. Cell Res."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1097\/PAS.0000000000000527","article-title":"Metastatic Malignant Melanoma with Complete Loss of Differentiation Markers (Undifferentiated\/Dedifferentiated Melanoma)","volume":"40","author":"Agaimy","year":"2016","journal-title":"Am. J. Surg. Pathol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"a012336","DOI":"10.1101\/cshperspect.a012336","article-title":"Translational Control in Cancer Etiology","volume":"5","author":"Ruggero","year":"2013","journal-title":"Cold Spring Harb. Perspect. Biol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"559","DOI":"10.1016\/j.ceb.2005.08.002","article-title":"Cell Migration in Tumors","volume":"17","author":"Yamaguchi","year":"2005","journal-title":"Curr. Opin. Cell Biol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"657","DOI":"10.1007\/s10585-007-9119-1","article-title":"Rho GTPases: Functions and Association with Cancer","volume":"24","author":"Ellenbroek","year":"2007","journal-title":"Clin. Exp. Metastasis."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"441","DOI":"10.1083\/jcb.200407076","article-title":"Molecular Mechanisms of Invadopodium Formation: The Role of the N-WASP\u2013Arp2\/3 Complex Pathway and Cofilin","volume":"168","author":"Yamaguchi","year":"2005","journal-title":"J. Cell Biol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"101975","DOI":"10.1016\/j.ctrv.2020.101975","article-title":"The Role of Exosomes in Metastasis and Progression of Melanoma","volume":"85","author":"Gowda","year":"2020","journal-title":"Cancer Treat. Rev."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1186\/s12943-019-0964-8","article-title":"Emerging Roles and Therapeutic Value of Exosomes in Cancer Metastasis","volume":"18","author":"Wu","year":"2019","journal-title":"Mol. Cancer."},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Shapanis, A., Lai, C., Smith, S., Coltart, G., Sommerlad, M., Schofield, J., Parkinson, E., Skipp, P., and Healy, E. (2020). Identification of proteins associated with development of metastasis from cutaneous squamous cell carcinomas (cSCCs) via proteomic analysis of primary cSCCs. Br. J. Dermatol.","DOI":"10.1111\/bjd.19485"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"4236","DOI":"10.1158\/1078-0432.CCR-15-2614","article-title":"OX40+ Regulatory T Cells in Cutaneous Squamous Cell Carcinoma Suppress Effector T-Cell Responses and Associate with Metastatic Potential","volume":"22","author":"Lai","year":"2016","journal-title":"Clin. cancer Res."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1681","DOI":"10.1056\/NEJMra022137","article-title":"Skin Cancers after Organ Transplantation","volume":"348","author":"Euvrard","year":"2003","journal-title":"N. Engl. J. Med."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"301","DOI":"10.1001\/archderm.139.3.301","article-title":"Defining the Clinical Course of Metastatic Skin Cancer in Organ Transplant Recipients: A Multicenter Collaborative Study","volume":"139","author":"Martinez","year":"2003","journal-title":"Arch. Dermatol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"929","DOI":"10.1158\/2326-6066.CIR-17-0279","article-title":"IL15 Infusion of Cancer Patients Expands The Subpopulation of Cytotoxic CD56bright NK Cells and Increases NK-Cell Cytokine Release Capabilities","volume":"5","author":"Dubois","year":"2017","journal-title":"Cancer Immunol. Res."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"595","DOI":"10.1038\/nri1901","article-title":"The Biology of Interleukin-2 and Interleukin-15: Implications for Cancer Therapy and Vaccine Design","volume":"6","author":"Waldmann","year":"2006","journal-title":"Nat. Rev. Immunol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1360","DOI":"10.4049\/jimmunol.1200593","article-title":"Heat shock protein 90 is critical for regulation of phenotype and functional activity of human T lymphocytes and NK cells","volume":"190","author":"Bae","year":"2013","journal-title":"J. Immunol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"3174","DOI":"10.4049\/jimmunol.1000749","article-title":"T-Bet and Eomesodermin are Required for T Cell-Mediated Antitumor Immune Responses","volume":"185","author":"Zhu","year":"2010","journal-title":"J. Immunol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"2981","DOI":"10.3389\/fimmu.2018.02981","article-title":"High Levels of Eomes Promote Exhaustion of Anti-Tumor CD8(+) T Cells","volume":"9","author":"Li","year":"2018","journal-title":"Front. Immunol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"92","DOI":"10.1038\/s41598-019-56542-4","article-title":"Melanoma Cell-Derived Exosomes in Plasma of Melanoma Patients Suppress Functions of Immune Effector Cells","volume":"10","author":"Sharma","year":"2020","journal-title":"Sci. Rep."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/21\/21\/8160\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T10:27:36Z","timestamp":1760178456000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/21\/21\/8160"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,10,31]]},"references-count":47,"journal-issue":{"issue":"21","published-online":{"date-parts":[[2020,11]]}},"alternative-id":["ijms21218160"],"URL":"https:\/\/doi.org\/10.3390\/ijms21218160","relation":{},"ISSN":["1422-0067"],"issn-type":[{"type":"electronic","value":"1422-0067"}],"subject":[],"published":{"date-parts":[[2020,10,31]]}}}