Prideapplication/xmlftp://ftp.pride.ebi.ac.uk/pride/data/archive/2016/12/PXD004624/sdrf.tsvftp://ftp.pride.ebi.ac.uk/pride/data/archive/2016/12/PXD004624/cachectic_melanoma_serum_1b.rawftp://ftp.pride.ebi.ac.uk/pride/data/archive/2016/12/PXD004624/cachectic_melanoma_serum_2a.rawftp://ftp.pride.ebi.ac.uk/pride/data/archive/2016/12/PXD004624/cachectic_melanoma_serum_2b.rawftp://ftp.pride.ebi.ac.uk/pride/data/archive/2016/12/PXD004624/cachectic_melanoma_serum_3a.rawftp://ftp.pride.ebi.ac.uk/pride/data/archive/2016/12/PXD004624/cachectic_melanoma_serum_3b.rawftp://ftp.pride.ebi.ac.uk/pride/data/archive/2016/12/PXD004624/cachectic_melanoma_serum_1a.rawftp://ftp.pride.ebi.ac.uk/pride/data/archive/2016/12/PXD004624/cachectic_melanoma_serum_3b.mzid.gzftp://ftp.pride.ebi.ac.uk/pride/data/archive/2016/12/PXD004624/cachectic_melanoma_serum_3a.mzid.gzftp://ftp.pride.ebi.ac.uk/pride/data/archive/2016/12/PXD004624/cachectic_melanoma_serum_1b.mzid.gzftp://ftp.pride.ebi.ac.uk/pride/data/archive/2016/12/PXD004624/cachectic_melanoma_serum_1a.mzid.gzftp://ftp.pride.ebi.ac.uk/pride/data/archive/2016/12/PXD004624/cachectic_melanoma_serum_2a.mzid.gzftp://ftp.pride.ebi.ac.uk/pride/data/archive/2016/12/PXD004624/cachectic_melanoma_serum_2b.mzid.gzftp://ftp.pride.ebi.ac.uk/pride/data/archive/2016/12/PXD004624/cachectic_melanoma_serum_3a.mgfftp://ftp.pride.ebi.ac.uk/pride/data/archive/2016/12/PXD004624/cachectic_melanoma_serum_2b.pride.mgf.gzftp://ftp.pride.ebi.ac.uk/pride/data/archive/2016/12/PXD004624/cachectic_melanoma_serum_3b.mgfftp://ftp.pride.ebi.ac.uk/pride/data/archive/2016/12/PXD004624/cachectic_melanoma_serum_1b.pride.mgf.gzftp://ftp.pride.ebi.ac.uk/pride/data/archive/2016/12/PXD004624/cachectic_melanoma_serum_1a.pride.mgf.gzftp://ftp.pride.ebi.ac.uk/pride/data/archive/2016/12/PXD004624/cachectic_melanoma_serum_1a.mgfftp://ftp.pride.ebi.ac.uk/pride/data/archive/2016/12/PXD004624/cachectic_melanoma_serum_1b.mgfftp://ftp.pride.ebi.ac.uk/pride/data/archive/2016/12/PXD004624/cachectic_melanoma_serum_2a.mgfftp://ftp.pride.ebi.ac.uk/pride/data/archive/2016/12/PXD004624/cachectic_melanoma_serum_3a.pride.mgf.gzftp://ftp.pride.ebi.ac.uk/pride/data/archive/2016/12/PXD004624/cachectic_melanoma_serum_3b.pride.mgf.gzftp://ftp.pride.ebi.ac.uk/pride/data/archive/2016/12/PXD004624/cachectic_melanoma_serum_2a.pride.mgf.gzftp://ftp.pride.ebi.ac.uk/pride/data/archive/2016/12/PXD004624/cachectic_melanoma_serum_2b.mgfftp://ftp.pride.ebi.ac.uk/pride/data/archive/2016/12/PXD004624/cachectic_melanoma_serum_2a.pride.mztab.gzftp://ftp.pride.ebi.ac.uk/pride/data/archive/2016/12/PXD004624/cachectic_melanoma_serum_3a.pride.mztab.gzftp://ftp.pride.ebi.ac.uk/pride/data/archive/2016/12/PXD004624/cachectic_melanoma_serum_2b.pride.mztab.gzftp://ftp.pride.ebi.ac.uk/pride/data/archive/2016/12/PXD004624/cachectic_melanoma_serum_1a.pride.mztab.gzftp://ftp.pride.ebi.ac.uk/pride/data/archive/2016/12/PXD004624/cachectic_melanoma_serum_3b.pride.mztab.gzftp://ftp.pride.ebi.ac.uk/pride/data/archive/2016/12/PXD004624/cachectic_melanoma_serum_1b.pride.mztab.gzprimaryOK200005560Christopher GernerBlood SerumSerum samples were routinely collected from patients with metastatic melanoma with high tumor load treated within a phase I/II trial (ClinicalTrials.gov Identifier: NCT01614301) after giving written informed consent. Serum samples were depleted employing Pierce™ Top 12 Abundant Protein Depletion Spin Columns (Thermo Fisher Scientific, USA). The depletion was performed according to the protocol of the manufacturer, using 7µL of serum per depletion. In the following, 250µL of depleted serum eluate containing not more than 25µg total protein amount was used for digestion. In-solution digestion was performed using 3 kDa MW cut off filters (Nanosep with Omega membrane, Pall, USA). After washing with 50 mM ammonium bicarbonate (Sigma Aldrich), proteins were reduced with 32mM dithiothreitol (Gerbu) for 30 min at 35°C on a thermal shaker (1000 rpm) and alkylated with 54mM 2-iodoacetamide solution (Sigma Aldrich) at 30°C for 45 min. Both, dithiothreitol and 2-iodoacetamide solutions were prepared with 8 M guanidinium hydrochloride (Sigma Aldrich) solution in 50nM ammonium bicarbonate. Afterwards, proteins were digested on the filter using a Trypsin/Lys-C Mix (MS grade; Promega) with a total enzyme to protein ratio of 1:20. For clean-up of resulting peptide samples C18 spin columns (Pierce™ C18 Spin Columns, Thermo Fisher Scientific, USA) were used and, after drying via vacuum centrifugation, the samples were stored at -20°C. Upon LC-MS analysis, the dried peptides were reconstituted in 5 µL of the equimolar 10 fmol standard peptide mix and 40 µL of mobile phase A (98% H2O, 2% ACN, 0.1% FA) for shotgun analysis. Digested peptides were separated by UltiMate 3000 RSLC nano System (Pre-column: Acclaim PepMap 100, C18 100 μm x 2 cm; Analytical column: Acclaim PepMap RSLC C18 75 μm x 50cm; Dionex, California, USA). Per injection, 1 µl of the sample was loaded on the pre-column with a flow rate of 10µl/min. For separation, peptides were eluted to the analytical column applying a gradient from 8 to 40% mobile phase B (80% ACN, 2% H2O, 0.1% FA) over 95 min and operating at a flow rate of 300nL/min. Data acquisition was conducted on a QExactive mass spectrometer (Thermo Fischer Scientific, USA) using a top 8 data dependent method. The full scan MS was acquired at a resolution of 70.000, the MS2 scan at 17.500, both at m/z 200.PrideChristopher GernerCOMPLETEUniversity of Vienna, Faculty of Chemistry, Department of Analytical Chemistry27879288 Muqaku B, Eisninger M, Meier SM, Tahir A, Prokop T, Haferkamp S, Slany A, Reichle A, Gerner C. Multi-omics analysis of serum samples demonstrates reprogramming of organ functions via systemic calcium mobilization and platelet activation in metastatic melanoma. Mol Cell Proteomics. 2016 Nov 22. pii: mcp.M116.063313University of Viennachristopher.gerner@univie.ac.atMass SpectrometryShotgun proteomicsMelanomaDamage signatureCalcium mobilizationMetastatic melanomaPlatelet activationCachexiaSerum analysisShotgun proteomicsMass spectrometryhttps://www.ebi.ac.uk/pride/archive/projects/PXD004624Not availableProteome Discoverer 1.4 (Thermo Fisher Scientific, Austria) running Mascot 2.4 (Matrix Science, UK) was used for protein identification. Protein identification was achieved searching against the SwissProt Database (version August 2014 with 20 194 entries) allowing a mass tolerance of 10ppm for MS spectra and 50mmu for MS/MS spectra as well as a maximum of 2 missed cleavages. Furthermore, search criteria included carbamidomethylation on cysteins as fixed modification and methionine oxidation as well as N-terminal protein acetylation as variable modifications.ProteomicsHomo Sapiens (human)christopher.gerner@univie.ac.atBiomedicalAustria10.6019/PXD004624Pathophysiologies of cancer-associated syndromes such as cachexia are poorly understood and no routine biomarkers have been established, yet. Using shotgun proteomics, known marker molecules including PMEL, CRP, SAA, and CSPG4 were found deregulated in patients with metastatic melanoma. Targeted analysis of 58 selected proteins with multiple reaction monitoring was applied for independent data verification. In three patients, two of which suffered from cachexia, a tissue damage signature was determined, consisting of nine proteins, PLTP, CD14, TIMP1, S10A8, S10A9, GP1BA, PTPRJ, CD44, and C4A, as well as increased levels of glycine and asparagine, and decreased levels of polyunsaturated phosphatidylcholine concentrations, as determined by targeted metabolomics. Remarkably, these molecules are known to be involved in key processes of cancer cachexia. Based on these results, we propose a model how metastatic melanoma may lead to reprogramming of organ functions via formation of platelet activating factors from long-chain polyunsaturated phosphatidylcholines under oxidative conditions and via systemic induction of intracellular calcium mobilization. Calcium mobilization in platelets was demonstrated to alter levels of several of these marker molecules. Additionally, platelets from melanoma patients proved to be in a rather exhausted state, and platelet-derived eicosanoids implicated in tumor growth were found massively increased in blood from three melanoma patients. Platelets were thus identified as important source of serum protein and lipid alterations in late stage melanoma patients. As a result, the proposed model describes the crosstalk between lipolysis of fat tissue and muscle wasting mediated by oxidative stress, resulting in the metabolic deregulations characteristic for cachexia.Multi-omics Analysis of Serum Samples Demonstrates Reprogramming of Organ Functions Via Systemic Calcium Mobilization and Platelet Activation in Metastatic Melanoma.Muqaku Besnik B, Eisinger Martin M, Meier Samuel M SM, Tahir Ammar A, Pukrop Tobias T, Haferkamp Sebastian S, Slany Astrid A, Reichle Albrecht A, Gerner Christopher CDIWS, PhrB photolyase activity, determination, Blood, classic hairy cell leukaemia, Monohydrate, Consent, Guanidine Sulfate (2:1), BOUND WATER, protein, Hydrogenchlorid, Serum, Tumor, pigmented epithelium, thomson., l(2)k09905, HOH, peptide, Cut, Membrane Tissues, Polypeptides, Techniques, hydrogen chloride, peptido, BANF, l(1)7Ba, l(1)7Bb, Method, B1, 1, 2, Williams-Beuren syndrome chromosomal region 6 protein, Min, 3, NUP96, protein aggregate, epithelium, Injectables, DmelCG42273, MIX, (R*, DmelCG8428, 3-hydroxy-5-estrane-17-carbonitrile, Spin, Divorced, C79325, kDa, peptides, 2610036I19Rik, membrane region, Tissue, 2610510L13Rik, E430039A18Rik, hypoplasia, pigmented retina, min, mAPC, Phosphate, Divorces, SCAN, CG11387, DNA cyclobutane dipyrimidine photolyase activity, SUPPRESSOR OF AUXIN RESISTANCE 3, AI047805, SPIN, fSAP152, Wasserstoffchlorid, column, Methodological Studies, Sputolysin, BTKAP1, Diws1t, ACN, D1, Acn, sample, n, CT, dihydridooxygen, Malignancies, Guanidine Sulfate (1:1), dihydrogen oxide, GTFII-I, Tumors, 6030441I21Rik, Membrane Tissue, PRE, Monohydrochloride, eluted material, Trypsin/K, deoxyribonucleic cyclobutane dipyrimidine photolyase activity, Ct, aqua, Dmel_CG7826, integral to membrane, Th, Guanidine Monohydroiodine, 4-dimercapto-2, Blood Serum, classic hairy cell leukemia, Procedure, BAP135, not genetically inherited, H2O, Benign, Cleland, Dm1, retinal pigment, SRF-Phox1-interacting protein, Chlorwasserstoff, dipyrimidine photolyase (photosensitive), BAP-135, metastatic melanoma, BcDNA:GH10590, retinal pigment layer, Dmel_CG7835, Mnb, MNB, l(2R)W5, MILD1, MS/MS, HCl, hydrogen hydroxide, Benign Neoplasms, fmol, Guanidine Phosphate, Guanidine Monohydrochloride, 3-Butanediol, Methodological, GtfII-I, AW124434, study protocol, beta Trypsin, Methodological Study, acqua, Malignant Neoplasms, R*)-1, phr A photolyase activity, l(2)W5, DNA-photoreactivating enzyme, Patient, WBS, Acetamide, Biocatalyst, CG8428, Polypeptide, Wasser, chlorane, other neoplasm, 4-Dimercapto-2, Cleland Reagent, rac-Dithiothreitol, l(1)VE614, Procedures, threo-1, chlorure d'hydrogene, Biocatalysts, Reagent, Neoplasms, Cleland's reagent, Benign Neoplasm, Gene, 4-dimercapto-, ACINUS, R*)-, photoreactivating enzyme activity, protein-containing complex, Malignant, 17alpha)-isomer, TFII-I, CG7826, agua, Bruton tyrosine kinase-associated protein 135, mass-to-charge ratio, method, Guanidium, reduced, Injection, integral component of membrane, method used in an experiment, Gene Products, CG7835, Studies, CG42273, IB291, stratum pigmentosa retinae, tiny, AA673430, Separated, cloruro de hidrogeno, Technique, Pro-Mega, Guanidium Chloride, Monohydroiodine, anatomical systems, MOS3, deoxyribocyclobutadipyrimidine pyrimidine-lyase activity, Malignancy, Acinus, PRECOCIOUS, Hydrogen chloride, Tissues, MS2, beta-Trypsin, F23A5.3, eau, kf, Solution, CD156, acinusL, Neoplasias, Injectable, Study, Enzyme, Monohydrobromide, Guanidinium Chloride, DmelCG11387, acinusS, Informed, Clients, region of membrane, peptidos, AA553322, BTK-associated protein 135, metastatic malignant melanoma, Guanidine Hydrochloride, 2-iodo-, F23A5_3, PTHB1, Cancer, small, 3-butanediol, WBSCR6, membrane, DYRK1, Guanidine Monohydrate, Guanidine Nitrate, Malignant Neoplasm, protein complex, Proteins, Clelands Reagent, chloridohydrogen, Client, Dithiothreitol, Guanidinium, Peptide, mKIAA0670, bnch, Dithiotreitol, l(2)k02511, polypeptide, [HCl], MODIFIER OF SNC1, native protein, C18, Protein, chemical analysis, DL-threo-1, deoxyribonucleic photolyase activity, Neoplasm, whole membrane, Hydrochloride, Guanidine Sulfite (1:1), Nitrate, 5alpha, MIXL, 25/11, Dyrk1, Vacuums, (3alpha, tandem MS, DTL, Cleland's, AU020952, Guanidine Monohydrobromide, Separation, transmembrane, DTT, 10^[-9], Guanidine, RPE, PRSS, Guanidine Sulfate, underdeveloped, photolyase activity, Separations, CC1, Tripcellim, Chloride, Cancers, Membrane, CD156a, sample population, ME-IV, p. pigmentosa retinae, Protein Gene Products, l(2)10403, plan specification, Cleland's Reagent, Gene Proteins, Trypure, Peptid, deoxyribonucleate pyrimidine dimer lyase (photosensitive), assay, [OH2], SCH, Sulfate, Serums, Neoplasia, hydrochloric acid, 3-OHECNcalcium ion (Ca2+) mobilization, Malignant Neoplasm, determination, malignant, Blood, Neoplasms, Proteins, Benign Neoplasm, Gene, Malignant Melanomas, Blood Serum, Serum, Tumor, Malignant, Client, element, melanoma (disease), Melanomas, Melanoma, Benign, melanoma, Malignant Melanoma, chemical analysis, Protein, Gene Products, Neoplasm, Platelet Activations, metastatic melanoma, organ, calcium mobilization, Activation, Malignancy, platelet activation, Naevocarcinoma, Benign Neoplasms, release of sequestered calcium ion into cytoplasm, Cancers, cytoplasmic release of stored calcium ion (Ca2+), release of sequestered calcium ion (Ca2+), Protein Gene Products, release of stored calcium ion (Ca2+), Neoplasias, Gene Proteins, blood coagulation, Patient, anatomical unit, Clients, body organ, Platelet, Activations, malignant melanoma, release of stored calcium ion (Ca2+) into cytoplasm, Malignancies, assay, cytoplasmic release of sequestered calcium ion (Ca2+), other neoplasm, metastatic malignant melanoma, Serums, Neoplasia, Cancer, Tumors, Malignant Neoplasms.2-amino-4-(methylsulfanyl)butanoic acid, AW549739, DL-Methionine, protein complex, immune system tolerance, Proteins, 2-Amino-4-(methylthio)butyric acid, L Isomer, FBN, Gene, protein, protein-containing complex, L-Isomer, ACMICD, L-Isomer Methionine, Drug Tolerance, Methionine, variable., native protein, Immune Tolerance, ECTOL1, Protein, Gene Products, Immunologic Tolerance, L-Methionine, MFS1, Methionin, Hmet, protein aggregate, WMS, Pedameth, Data Base, WMS2, Met, C79691, M, protein amino acid acetylation, Sciences, MASCOT, MASS, Lccp, Protein Gene Products, OCTD, mKIAA0989, Gene Proteins, Self Tolerance, 2-amino-4-(methylthio)butanoic acid, Tolerance, SSKS, alpha-amino-gamma-methylmercaptobutyric acid, GPHYSD2, metionina, Runnings, Racemethionine, Liquimeth, drug tolerance, SGS, Immunological ToleranceBODYFAT, nucleocytoplasm, Surrogate Endpoints, Pgp-1, Laboratory, Aminoessigsaeure, Muscle hypotrophy, PGP-1, Gly, Choline phosphatide, Metabonomics, growth and development, Scc-1, hyaluronate receptor, BDPLT1, Tumor, BDPLT3, MAGE-E1 antigen, Extracellular matrix receptor III, MSK16, Oxidative DNA, Oxidative, Biological, R-PTP-ETA, 1, 2, monocyte differentiation antigen CD14, Nitro-Oxidative Stresses, B8, DNA Damage, PGP-I, organ, DL-Asparagine, asparagina, G, D1S181E, Glycine, N, L-Asparagine, Tissue, Oxidative Cleavage, HEL-141, myeloid cell-specific leucine-rich glycoprotein, wasting - muscle, ch, Amyotrophy, decreased, Oxidative Stresses, MCSPG, HERMES, Glycocoll, Bpife, BET, release of stored calcium ion (Ca2+) into cytoplasm, stage, Phosphatidylcholine, cytoplasmic release of sequestered calcium ion (Ca2+), Hyaluronate receptor, OD107, BPIFE, Tumors, Cobalt Salt Glycine, Viral, Epididymis luminal protein 141, anatomical protrusion, Glycine Phosphate, GPIbA, CD44 antigen, Monosodium Salt Glycine, Malignant Melanomas, Copper Salt Glycine, multicellular organismal lipid catabolic process, DmelCG7664, Benign, Marker, ly-24, DAMAGE, Hepatocellular carcinoma-associated protein 1, GPIba, simple tissue, DNA Oxidative Damages, Acid, HUTCH-I, End Points, Glycine Sulfate (3:1), Glycerophospholipids, Benign Neoplasms, Immunologic, Cobalt Salt, 2-amino-3-carbamoylpropanoic acid, Laboratory Marker, GPIb-alpha, Malignant Neoplasms, Nitro-Oxidative, polyunsaturated phosphatidylcholine, Muscular atrophy, Platelet, DNA, EPA, PTPbeta2, platelet, other neoplasm, GP1B, Aa1249, Oxidative Damage, CD42b-alpha, lipids, TIMP-1, EPO, Cysteine-rich protein 1, DBPLT3, Peptidomics, Antioxidative, Clinical Marker, Neoplasms, developmental stage, 35F(AT)[[17]], Hasp, AI450271, protein-containing complex, melanoma (disease), IN, CYRP, urinary form, 4732461B14Rik, Gene Products, Phosphatidyl, Oxidative Damages, Injury, Clinical, dysfunction, Naevocarcinoma, Monosodium Salt, AI847422, Ac1-114, Neoplasias, l(2)k03505, Phagocytic glycoprotein I, CSPG8, anatomical unit, Antioxidative Stresses, 0610010I23Rik, body organ, bodyfat, AI255847, GPIbalpha, Thrombocyte, metastatic malignant melanoma, Biologic, Cancer, Malignant Neoplasm, 3-sn-Phosphatidylcholine, whole blood, Phagocytic glycoprotein 1, Monopotassium Salt Glycine, Serum Markers, Proteins, Copper Salt, Phosphatidyl Cholines, Phosphoglycerides, NG2, Anti-oxidative Stresses, Amyotrophy involving the extremities, Immune Marker, AN2, MT, native protein, Surrogate End Point, Icosanoid, amyotrophia, Oxidative Nitrative Stresses, Malignant Melanoma, chemical analysis, Neoplasm, Cholines, CD148, HCELL, Biologic Markers, Crp, CRP, primary cancer, Muscle wasting, Anti-oxidative Stress, Neurogenic muscular atrophy, DNA Oxidative Damage, RGD1560259, Surrogate, MS:35F.AT17, increased number, extracellular matrix receptor III, Endpoints, bHLHe63, postnatal growth, Monopotassium Salt, Cancers, HMW-MAA, cytoplasmic release of stored calcium ion (Ca2+), Glyzin, enucleate thrombocyte, 4-diamino-4-oxobutanoic acid, malignant tumor, Phosphatidyl Choline, Gene Proteins, AP4, dAP-4, adipose, Ac2-069, Aminoacetic, Glykokoll, Stress, DBMT1, PC, Neoplasia, Calcium Salt, C77570, GP-Ib alpha, GP90 lymphocyte homing/adhesion receptor, Immune Markers, DNA Oxidative, Ly-24, Glycine Carbonate (2:1), Biological Markers, Viral Marker, HDLCQ9, AU023126, AP-4, Calcium Salt Glycine, determination, H2N-CH2-COOH, Epican, DEP-1, Blood, CD44A, postnatal development, Biochemical, Metabonomic, Endpoint, Nitrative Stress, Phosphatidyl-N-trimethylethanolamine, CG7664, protein, Monoammonium, Serum, Monosodium, Damage, element, BSS, Laboratory Markers, especially in the lower limbs, Thrombocytes, melanoma, Calcium Salt (2:1), Lymphocyte antigen 24, Nitro-Oxidative Stress, Monoammonium Salt Glycine, multicellular organism lipid catabolic process, gp300, protein aggregate, Oxidative Injury, fatty tissue, present in fewer numbers in organism, fat tissue, DEP1, Pgp1, multicellular organismal biosynthetic process, increased, single-organism biosynthetic process, Lecithin, Oxidative Injuries, antigen CD42b-alpha, adipose system, CD42B, long, AW743261, Phosphate, release of sequestered calcium ion into cytoplasm, MCSP, LHR, Oxidative DNA Damages, Estimated, CD14, heparan sulfate proteoglycan, ASN, Asn, Anti-oxidative, Oxidative Stress Injuries, Immune, Markers, anucleate thrombocyte, malignant neoplasm, HCA1, Viral Markers, CD42b, muscle wasting, MDU2, MDU3, Malignancies, associated, METAA, Surrogate Endpoint, PLATEST, Icosanoids, CRP4, CRP2, CRP1, Blood Platelet, MC56, Neurogenic muscle atrophy, Biochemical Markers, Blood Serum, aminoethanoic acid, Biologic Marker, hermes antigen, results, Multiple Reaction Monitoring, GP90 lymphocyte homing|adhesion receptor, AW146109, Hermes antigen, Body Fat, Melanoma, GP1BA, Oxidative and Nitrosative Stress, neurogenic, Wasting syndrome, Lipid, HCI, CSRP, crp.4a, metastatic melanoma, internal to cell, SCC1, Scc1, CD44, Ab1-341, CDW44, l(2)00232, MIC4, growth pattern, non-developmental growth, Hgly, Byp, Timp, Muscle atrophy, Crpd, CDw44, Patient, Biochemical Marker, spine, ECMR-III, blood platelet, Oxidative Stress Injury, RPTPJ, Wasting syndrome., mMage-e1, Platelets, accessory, TIMP, AW121933, Ba2-693, CIB8, Oxidative Stress, CRP-[a], Sodium Hydrogen Carbonate, Clinical Markers, Clgi, Lecithol, RHAMM, Monopotassium, Benign Neoplasm, Antioxidative Stress, Gene, CLGI, l(2)35Fd, fat, Malignant, supernumerary, Monocyte differentiation antigen CD14, Surrogate End Points, protrusion, Stresses, Lipolyses, Surrogate Markers, VWDP, l(2)SH1614, Oxidative Nitrative, reduced, Stress Injury, subnumerary, ESP1, thrombocyte, l(2)k00809, Oxidative Cleavages, Glycine Hydrochloride (2:1), Metabolomic, Choline Glycerophospholipids, protoplasm, Ptpb2, Biomarker, calcium mobilization, epican, Glycine Hydrochloride, MRM, protoplast, Malignancy, Biological Marker, phagocytic glycoprotein I, decreased number, Asparagin, release of stored calcium ion (Ca2+), Immunologic Markers, Muscle degeneration, CRP-[b], Salt Glycine, Glycin, phagocytic glycoprotein 1, Anti oxidative Stress, p80, phosphatidylcholines, Oxidative DNA Damage, Clients, Phospholutein, Leimzucker, 2-aminoacetic acid, Choline, Immunologic Marker, BG:DS02740.3, Monoammonium Salt, calcium ion (Ca2+) mobilization, Glycine Phosphate (1:1), HPTPeta, ptx1, protein complex, malignant, Alpha-dystrobrevin-associated MAGE Protein, Aminoacetic acid, End Point, Eicosanoid, Client, Heparan sulfate proteoglycan, development, Melanomas, Oxidative Nitrative Stress, Glycine Carbonate (1:1), Ac1262, Myeloid cell-specific leucine-rich glycoprotein, Protein, Hydrochloride, membrane-bound form, SAA, 2-Diacyl-sn-glycero-3-phosphocholine, Aminoacetic Acid, Serum Marker, Hlp, glycoprotein Ibalpha, l(2)SH2 1614, pathophysiology, Ab2-196, Monolithium Salt, release of sequestered calcium ion (Ca2+), Cleavage, Choline Phosphoglycerides, Surrogate Marker, Protein Gene Products, lymphocyte antigen 24, present in greater numbers in organism, fatty depot, MEL-CSPG, malignant melanoma, assay, PTX1, Nitro Oxidative Stress, growth, SerumsBODYFAT, nucleocytoplasm, Surrogate Endpoints, syndrome associated with disease or disorder, Pgp-1, Laboratory, Aminoessigsaeure, Muscle hypotrophy, PGP-1, Gly, Choline phosphatide, Metabonomics, growth and development, Scc-1, hyaluronate receptor, BDPLT1, sci, Tumor, BDPLT3, MAGE-E1 antigen, Extracellular matrix receptor III, MSK16, Oxidative DNA, Oxidative, Biological, C4AD, R-PTP-ETA, HOW, How, 1, 2, monocyte differentiation antigen CD14, Nitro-Oxidative Stresses, B8, C4A6, C4A4, DNA Damage, C4A3, PGP-I, C4A2, organ, DL-Asparagine, asparagina, molecules, G, D1S181E, Glycine, N, L-Asparagine, Tissue, C4, Oxidative Cleavage, stru, HEL-141, myeloid cell-specific leucine-rich glycoprotein, Molekuel, l(3)S053606, wasting - muscle, Amyotrophy, Oxidative Stresses, MCSPG, HERMES, Glycocoll, Bpife, Symptom Clusters, BET, release of stored calcium ion (Ca2+) into cytoplasm, Blood Protein, stage, Phosphatidylcholine, cytoplasmic release of sequestered calcium ion (Ca2+), Hyaluronate receptor, OD107, BPIFE, Tumors, Cobalt Salt Glycine, Viral, Epididymis luminal protein 141, anatomical protrusion, Glycine Phosphate, GPIbA, CD44 antigen, Monosodium Salt Glycine, Malignant Melanomas, Copper Salt Glycine, multicellular organismal lipid catabolic process, DmIKKgamma, DmelCG7664, Benign, symptom cluster, Marker, ly-24, dIKK, DAMAGE, Hepatocellular carcinoma-associated protein 1, GPIba, simple tissue, DNA Oxidative Damages, Acid, HUTCH-I, End Points, Glycine Sulfate (3:1), Glycerophospholipids, IKK-gamma, Benign Neoplasms, Immunologic, Cobalt Salt, 2-amino-3-carbamoylpropanoic acid, Laboratory Marker, GPIb-alpha, Malignant Neoplasms, Nitro-Oxidative, polyunsaturated phosphatidylcholine, Muscular atrophy, Platelet, DNA, EPA, PTPbeta2, platelet, other neoplasm, GP1B, Aa1249, Oxidative Damage, CD42b-alpha, lipids, TIMP-1, EPO, Cysteine-rich protein 1, DBPLT3, Peptidomics, Antioxidative, Clinical Marker, Neoplasms, developmental stage, 35F(AT)[[17]], Hasp, Serum Protein, AI450271, syndromic disease or disorder, dIKK-gamma, melanoma (disease), IN, CYRP, urinary form, DmIKK-gamma, 4732461B14Rik, symptom clusters, Gene Products, Phosphatidyl, Oxidative Damages, Injury, Clinical, CO4, Naevocarcinoma, Monosodium Salt, syndrome, AI847422, syndromes, Ac1-114, Symptom, CPAMD2, Neoplasias, Plasma Protein, l(2)k03505, Phagocytic glycoprotein I, CSPG8, anatomical unit, Antioxidative Stresses, 0610010I23Rik, body organ, bodyfat, AI255847, GPIbalpha, Thrombocyte, Biologic, Cancer, Malignant Neoplasm, 3-sn-Phosphatidylcholine, whole blood, Phagocytic glycoprotein 1, Monopotassium Salt Glycine, Serum Markers, Proteins, Copper Salt, Phosphatidyl Cholines, Phosphoglycerides, NG2, qkr, Anti-oxidative Stresses, l(3)S090417, Amyotrophy involving the extremities, Immune Marker, IKKgamma, AN2, MT, C4-1, Surrogate End Point, Symptom Cluster, Icosanoid, amyotrophia, Oxidative Nitrative Stresses, Malignant Melanoma, KH93F, chemical analysis, Neoplasm, Cholines, CD148, HCELL, Biologic Markers, Crp, CRP, primary cancer, Muscle wasting, Anti-oxidative Stress, Neurogenic muscular atrophy, DNA Oxidative Damage, RGD1560259, Surrogate, MS:35F.AT17, Dmikkgamma, extracellular matrix receptor III, Endpoints, bHLHe63, postnatal growth, Monopotassium Salt, Cancers, HMW-MAA, cytoplasmic release of stored calcium ion (Ca2+), Glyzin, enucleate thrombocyte, CG16910, 4-diamino-4-oxobutanoic acid, malignant tumor, Phosphatidyl Choline, Gene Proteins, AP4, dAP-4, adipose, Ac2-069, Aminoacetic, Glykokoll, Stress, DBMT1, PC, Neoplasia, Calcium Salt, C77570, GP-Ib alpha, GP90 lymphocyte homing/adhesion receptor, Immune Markers, cluster, DNA Oxidative, Ly-24, Glycine Carbonate (2:1), Biological Markers, Viral Marker, HDLCQ9, AU023126, AP-4, Calcium Salt Glycine, determination, H2N-CH2-COOH, Epican, DEP-1, Feature, Blood, CD44A, postnatal development, Biochemical, Metabonomic, Endpoint, Nitrative Stress, Phosphatidyl-N-trimethylethanolamine, CG7664, neutral molecular compounds, Monoammonium, Serum, Monosodium, Damage, element, BSS, C4S, Laboratory Markers, especially in the lower limbs, Thrombocytes, melanoma, Calcium Salt (2:1), Lymphocyte antigen 24, Nitro-Oxidative Stress, C4b, Monoammonium Salt Glycine, symptom, multicellular organism lipid catabolic process, gp300, RG, Oxidative Injury, fatty tissue, molecule, IKKg, l(3)j5D5, fat tissue, DEP1, Pgp1, KEY, Key, multicellular organismal biosynthetic process, molecula, 24B, single-organism biosynthetic process, Lecithin, Oxidative Injuries, antigen CD42b-alpha, adipose system, CD42B, AW743261, Phosphate, release of sequestered calcium ion into cytoplasm, MCSP, LHR, Oxidative DNA Damages, Estimated, CD14, CG10293, heparan sulfate proteoglycan, ASN, Asn, Anti-oxidative, l(3)j5B5, Oxidative Stress Injuries, Immune, Markers, anucleate thrombocyte, malignant neoplasm, HCA1, syndromic disease, Viral Markers, CD42b, muscle wasting, MDU2, MDU3, Malignancies, METAA, 0904/17, Surrogate Endpoint, PLATEST, Icosanoids, CRP4, CRP2, CRP1, Blood Platelet, MC56, Neurogenic muscle atrophy, Biochemical Markers, Clusters, aminoethanoic acid, Biologic Marker, hermes antigen, Multiple Reaction Monitoring, GP90 lymphocyte homing|adhesion receptor, AW146109, Hermes antigen, Body Fat, Melanoma, GP1BA, SZ1, Oxidative and Nitrosative Stress, neurogenic, Wasting syndrome, Lipid, HCI, Kenny, CSRP, crp.4a, internal to cell, SCC1, Scc1, CD44, Ab1-341, CDW44, l(2)00232, MIC4, growth pattern, non-developmental growth, Hgly, Byp, Features, clusters, Timp, Muscle atrophy, Crpd, metastatic, CDw44, DmelCG16910, Syndromes, Cluster, Patient, Biochemical Marker, spine, ECMR-III, blood platelet, anon-EST:Liang-2.39, Oxidative Stress Injury, RPTPJ, Wasting syndrome., mMage-e1, Platelets, TIMP, AW121933, Ba2-693, CIB8, Oxidative Stress, CRP-[a], Sodium Hydrogen Carbonate, Clinical Markers, Clgi, Lecithol, P62, RHAMM, Monopotassium, Benign Neoplasm, Antioxidative Stress, Gene, CLGI, l(2)35Fd, fat, Malignant, Monocyte differentiation antigen CD14, Surrogate End Points, protrusion, Stresses, Lipolyses, Surrogate Markers, VWDP, l(2)SH1614, Oxidative Nitrative, Stress Injury, ESP1, thrombocyte, l(2)k00809, Oxidative Cleavages, Glycine Hydrochloride (2:1), dmIKKgamma, Metabolomic, IKK[[gamma]], Choline Glycerophospholipids, protoplasm, Ptpb2, Biomarker, calcium mobilization, epican, Glycine Hydrochloride, l(3)s2612, MRM, protoplast, Malignancy, Biological Marker, phagocytic glycoprotein I, Serum Proteins, Plasma Proteins, Asparagin, release of stored calcium ion (Ca2+), Immunologic Markers, Muscle degeneration, CRP-[b], Salt Glycine, Glycin, phagocytic glycoprotein 1, IKK, Anti oxidative Stress, p80, phosphatidylcholines, Oxidative DNA Damage, Clients, DmelCG10293, Phospholutein, Leimzucker, 2-aminoacetic acid, Characteristics, Choline, Immunologic Marker, BG:DS02740.3, Monoammonium Salt, calcium ion (Ca2+) mobilization, Glycine Phosphate (1:1), HPTPeta, ptx1, clone 2.39, malignant, Alpha-dystrobrevin-associated MAGE Protein, Aminoacetic acid, End Point, Eicosanoid, Client, Heparan sulfate proteoglycan, development, Melanomas, Oxidative Nitrative Stress, Glycine Carbonate (1:1), Characteristic, Ac1262, Myeloid cell-specific leucine-rich glycoprotein, Protein, Hydrochloride, membrane-bound form, 2-Diacyl-sn-glycero-3-phosphocholine, who, Plasma, Aminoacetic Acid, Serum Marker, Hlp, glycoprotein Ibalpha, l(2)SH2 1614, Ab2-196, Who/How, Monolithium Salt, release of sequestered calcium ion (Ca2+), Cleavage, Choline Phosphoglycerides, Surrogate Marker, Protein Gene Products, lymphocyte antigen 24, fatty depot, qkr[93F], MEL-CSPG, malignant melanoma, assay, PTX1, Nitro Oxidative Stress, growthPanomics, organ, Multi Omics, calcium ion (Ca2+) mobilization, calcium mobilization, Integrative-Omics, determination, Activation, malignant, Blood, platelet activation, Integrative, release of sequestered calcium ion into cytoplasm, Omics, Malignant Melanomas, cytoplasmic release of stored calcium ion (Ca2+), Blood Serum, Serum, release of sequestered calcium ion (Ca2+), Naevocarcinoma., Integrative Omics, Malignant, element, Multi-Omics, release of stored calcium ion (Ca2+), melanoma (disease), metastatic, Melanomas, blood coagulation, Melanoma, melanoma, anatomical unit, Malignant Melanoma, chemical analysis, body organ, Multi-Omic, Pan Omics, Platelet, Activations, Pan-Omics, malignant melanoma, release of stored calcium ion (Ca2+) into cytoplasm, assay, Platelet Activations, cytoplasmic release of sequestered calcium ion (Ca2+), Serums556falseMulti-omics analysis of serum samples demonstrates reprogramming of organ functions via systemic calcium mobilization and platelet activation in metastatic melanoma patients – proteins from serum samples of melanoma patients with high tumor loadPathophysiology of cancer-associated syndroms such as cachexia is poorly understood and no routine biomarkers have been established, yet. Using shotgun proteomics, known marker molecules including PMEL, CRP, SAA and CSPG4 were found deregulated in patients with metastatic melanoma. Targeted analysis of 58 selected proteins with multiple reaction monitoring was applied for independent data verification. In three patients, two of which suffered from cachexia, a tissue damage signature was determined, consisting on nine proteins, PLTP, CD14, TIMP1, S10A8, S10A9, GP1BA, PTPRJ, CD44 and CO4A, as well as increased levels of glycine and asparagine, and decreased levels of polyunsaturated phosphatidylcholine concentrations, as determined by targeted metabolomics. Remarkably, these molecules are known to be involved in key processes of cancer cachexia. Based on these results, we propose a model how metastatic melanoma may lead to reprogramming of organ functions via formation of platelet activating factors from long-chain polyunsaturated phosphatidylcholines under oxidative conditions and via systemic induction of intracellular calcium mobilization. Calcium mobilization in platelets was demonstrated to regulate several of these marker molecules. Additionally, platelets from melanoma patients proved to be in a rather exhausted state, and platelet-derived eicosanoids implicated in tumor growth were found massively increased in blood from three melanoma patients. Platelets were thus identified as important source of serum protein and lipid alterations in late stage melanoma patients. As a result, the proposed model describes the crosstalk between lipolysis of fat tissue and muscle wasting mediated by oxidative stress, resulting in the metabolic deregulations characteristic for cachexia.2016-12-222016-07-21PXD004624NEWT:3555NEWT:71647NEWT:330879NEWT:260201NEWT:35554NCBITaxon:12939NEWT:32046NEWT:544496NEWT:59529NEWT:2042546NEWT:32049NEWT:1392696NEWT:259447NEWT:295546NCBITaxon:2719036NEWT:45351NEWT:445974NEWT:43179NEWT:180454NEWT:5722NCBITaxon:1280NEWT:112503NEWT:1129NEWT:309807NEWT:10245NEWT:55153NEWT:89184NEWT:309800NEWT:281395NEWT:1211601NEWT:876138NEWT:44271NEWT:193516NEWT:351581NEWT:43186NEWT:428146NEWT:111205NEWT:1117NEWT:498257NEWT:10036NEWT:1590NEWT:498019NEWT:1351NEWT:1438992NEWT:1352NEWT:2649997NEWT:1147161NEWT:661410NEWT:638632NEWT:43150NEWT:263737NEWT:224326NEWT:1333499NEWT:376619NCBITaxon:79857NEWT:1096976NEWT:5702NEWT:95648NEWT:1589NEWT:135622NEWT:1349NEWT:35786NEWT:1580NEWT:399784NEWT:96731NEWT:383379NEWT:1401257NEWT:418106NEWT:10029NEWT:913645NEWT:44491NEWT:641809NEWT:27933NEWT:556484NEWT:317447NEWT:4688NEWT:7955NEWT:111225NEWT:7719NEWT:7959NEWT:2261NEWT:868565NEWT:135674NEWT:94323NEWT:31156NEWT:3112NEWT:79329NEWT:4442NEWT:192875NEWT:1214915NEWT:30069NEWT:12637NEWT:59729NEWT:2164133NEWT:284218NEWT:295105NEWT:108061NEWT:60711NEWT:1316931NEWT:224308NEWT:3347NEWT:511145NEWT:160621NEWT:212790NEWT:931281NEWT:4432NEWT:5762NEWT:5763NEWT:658457NEWT:1310161NEWT:77133NEWT:295358NEWT:145481NEWT:1310165NEWT:29058NCBITaxon:79824NEWT:2246NEWT:2652724NEWT:1912919NEWT:5757NEWT:68415NCBITaxon:4563NEWT:5755NEWT:44688NEWT:44689NEWT:44447NEWT:752555NEWT:498211NEWT:5759NEWT:347256NEWT:1736231NEWT:5518NEWT:398007NEWT:1527468NEWT:1392NEWT:498217NEWT:498216NEWT:2242NEWT:11320NEWT:286NEWT:391619NEWT:246196NEWT:287NEWT:246197NEWT:1367269NEWT:145458NEWT:633149NEWT:1149786NEWT:10239NEWT:68895NEWT:44685NEWT:161934NEWT:4897NEWT:1148NEWT:5744NEWT:72901NEWT:213863NEWT:5508NEWT:3329NEWT:5507NEWT:410661NEWT:55571NEWT:35500NEWT:1235816NEWT:1140NCBITaxon:2157NEWT:1143NEWT:4896NEWT:1287689NEWT:1390NEWT:11557NEWT:1094343NEWT:1462472NEWT:1336795NEWT:644042NEWT:294NEWT:1773NEWT:1182590NEWT:3712NEWT:82380NEWT:3711NEWT:935293NEWT:375146NEWT:270643NEWT:2065263NEWT:177437NEWT:1772NEWT:10418NEWT:118698NEWT:1616117NEWT:263NEWT:118696NEWT:34865NEWT:52283NEWT:11988NEWT:284812NEWT:8175NEWT:400667NEWT:43330NEWT:1603293NEWT:408169NEWT:44664NEWT:47946NEWT:459758NEWT:3702NEWT:1245466NEWT:243277NEWT:1246791NEWT:7067NEWT:118694NEWT:586722NEWT:2850NEWT:118691NEWT:34871NEWT:33548NEWT:274NEWT:7070NCBITaxon:287NEWT:408172NEWT:408170NEWT:96794NEWT:3708NEWT:332648NEWT:44670NEWT:536231NEWT:376219NEWT:219813NEWT:1510NEWT:1436733NEWT:460519NEWT:1247411NEWT:1515NEWT:572307NEWT:1432138NEWT:9238NEWT:1424507NEWT:1194599NEWT:272844NEWT:1303443NEWT:9483NEWT:333760NEWT:485NEWT:34607NEWT:56636NEWT:1513458NEWT:1233681NEWT:2709072NCBITaxon:40559NEWT:506599NEWT:2853422NEWT:81077NEWT:84588NEWT:1679718NEWT:480NEWT:65349NEWT:67767NEWT:46835NEWT:109757NEWT:582580NEWT:300852NEWT:294607NEWT:1502NEWT:128017NEWT:376686NEWT:95486NEWT:508771NEWT:1883446NEWT:253NCBITaxon:2759NEWT:1233435NEWT:93061NEWT:93062NEWT:34613NEWT:548470NCBITaxon:4932NEWT:1748NEWT:109760NEWT:29031NEWT:943274NEWT:644223NEWT:1263082NEWT:235443NEWT:108458NEWT:5936NEWT:272623NEWT:272624NEWT:320637NEWT:886559NEWT:3750NEWT:55521NEWT:983964NEWT:118499NEWT:11706NEWT:32644NEWT:527796NEWT:1130798NEWT:55529NEWT:499175NEWT:109779NEWT:3745NEWT:1715989NCBITaxon:4751NEWT:476272NEWT:3747NEWT:195051NEWT:3988NEWT:1116234NEWT:561007NEWT:1255228NEWT:649908NEWT:410289NEWT:373153NEWT:3983NEWT:203696NEWT:472NEWT:352472NEWT:97441NEWT:1154756NEWT:1071661NEWT:1202531NEWT:1202532NEWT:360094NEWT:1408223NEWT:470NEWT:1408224NEWT:41364NEWT:5911NEWT:1313NEWT:1218097NEWT:1080348NCBITaxon:50557NEWT:1314NEWT:39251NEWT:39491NEWT:212142NCBITaxon:5811NEWT:29491NEWT:101841NEWT:153481NEWT:2014887NEWT:1499105NEWT:33952NEWT:445NEWT:153009NEWT:261756NEWT:571256NEWT:40483NEWT:63366NEWT:63367NEWT:688333NEWT:215402NCBITaxon:548681NEWT:318586NCBITaxon:5820NEWT:1547NEWT:272634NEWT:198107NEWT:9031NEWT:27292NEWT:1872122NEWT:1308NEWT:7091NEWT:1034015NEWT:760568NEWT:141262NEWT:108931NEWT:1293497NEWT:1055524NEWT:4087NEWT:9778NEWT:306NEWT:150475NEWT:303NEWT:267872NEWT:97477NEWT:7111NEWT:347515NEWT:172269NEWT:9534NEWT:6269NEWT:5180NEWT:256737NEWT:4090NEWT:4092NEWT:9541NEWT:8694NEWT:4093NEWT:33936NEWT:4096NEWT:8692NEWT:2903NEWT:185579NEWT:941442NEWT:536088NEWT:13076NEWT:1226408NEWT:7108NEWT:40479NEWT:43989NEWT:4076NEWT:142615NEWT:317NEWT:1006581NEWT:33940NEWT:885318NEWT:39488NEWT:550NEWT:4081NEWT:273068NEWT:554NEWT:98334NEWT:451516NEWT:552NEWT:231663NEWT:4084NEWT:1325291NEWT:63577NEWT:36185NEWT:1054211NEWT:1225786NEWT:7574NEWT:1715256NEWT:30640NEWT:575412NEWT:929793NEWT:1507179NEWT:29204NEWT:28112NEWT:114155NEWT:6493NEWT:6494NEWT:6491NEWT:507601NEWT:520NEWT:186441NEWT:634955NEWT:643680NEWT:214092NCBITaxon:6157NEWT:6239NEWT:13095NEWT:162425NEWT:104105NEWT:216257NEWT:102169NEWT:208893NEWT:9986NEWT:4054NEWT:8654NEWT:8658NEWT:1268063NEWT:8657NEWT:8655NEWT:5147NEWT:98351NEWT:1263854NEWT:118503NEWT:2059687NEWT:160488NEWT:63558NEWT:28104NEWT:207559NEWT:407821NCBITaxon:2NEWT:85057NEWT:985076NEWT:568708NEWT:1215323NEWT:986NEWT:52641NEWT:7159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