{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,9,20]],"date-time":"2025-09-20T10:13:53Z","timestamp":1758363233253,"version":"3.44.0"},"reference-count":117,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2025,8,5]],"date-time":"2025-08-05T00:00:00Z","timestamp":1754352000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Quant. Biol."],"published-print":{"date-parts":[[2025,12]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Cancer is a complex and heterogeneous disease characterized by various genetic and epigenetic alterations. Early diagnosis, accurate subtyping, and staging are essential for effective, personalized treatment and improved survival rates. Traditional diagnostic methods, such as biopsies, are invasive and carry operational risks that hinder repeated use, underscoring the need for noninvasive and personalized alternatives. In response, this study integrates transcriptomic data into human genome\u2010scale metabolic models (GSMMs) to derive patient\u2010specific flux distributions, which are then combined with genomic, proteomic, and fluxomic (JX) data to develop a robust multi\u2010omic classifier for lung cancer subtyping and early diagnosis. The JX classifier is further enhanced by analyzing heterogeneous datasets from RNA sequencing and microarray analyses derived from both tissue samples and cell culture experiments, thereby enabling the identification of key marker features and enriched pathways such as lipid metabolism and energy production. This integrated approach not only demonstrates high performance in distinguishing lung cancer subtypes and early\u2010stage disease but also proves robust when applied to limited pancreatic cancer data. By linking genotype to phenotype, GSMM\u2010driven flux analysis overcomes challenges related to metabolome data scarcity and platform variability by proposing marker processes and reactions for further investigation, ultimately facilitating noninvasive diagnostics and the identification of actionable biomarkers for targeted therapeutic intervention. These findings offer significant promise for streamlining clinical workflows and enabling personalized therapeutic strategies, and they highlight the potential of our versatile workflow for unveiling novel biomarker landscapes in less studied diseases.<\/jats:p>","DOI":"10.1002\/qub2.70012","type":"journal-article","created":{"date-parts":[[2025,8,6]],"date-time":"2025-08-06T05:26:06Z","timestamp":1754457966000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Multi\u2010omic data integration and exploiting metabolic models using systems biology approach increase precision in subtyping and early diagnosis of cancer"],"prefix":"10.1002","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3091-3797","authenticated-orcid":false,"given":"Ezgi","family":"Tan\u0131l","sequence":"first","affiliation":[{"name":"Department of Genetics and Bioengineering Yeditepe University  Istanbul T\u00fcrkiye"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9157-8662","authenticated-orcid":false,"given":"Emrah","family":"Nikerel","sequence":"additional","affiliation":[{"name":"Department of Genetics and Bioengineering Yeditepe University  Istanbul T\u00fcrkiye"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2025,8,5]]},"reference":[{"key":"e_1_2_10_2_1","unstructured":"Surveillance Epidemiology and End Results (SEER) Program.Cancer stat facts: lung and bronchus cancer.National Cancer Institute."},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jprot.2016.05.030"},{"key":"e_1_2_10_4_1","unstructured":"Surveillance Epidemiology and End Results (SEER) Program.Cancer Stat Facts: Pancreatic Cancer. National Cancer Institute."},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.3748\/wjg.v24.i19.2047"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.3390\/cancers12102767"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1007\/978-3-031-22903-9_24"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.1186\/s40364-023-00507-3"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2024.1331215"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12967-024-05908-y"},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.1039\/C4MB00659C"},{"key":"e_1_2_10_12_1","article-title":"Targeted therapy for non\u2010small cell lung cancer: current standards and the promise of the future","volume":"4","author":"Chan BA","year":"2015","journal-title":"Transl Lung Cancer Res"},{"key":"e_1_2_10_13_1","doi-asserted-by":"publisher","DOI":"10.7314\/APJCP.2016.17.2.835"},{"key":"e_1_2_10_14_1","doi-asserted-by":"publisher","DOI":"10.1158\/1940-6207.CAPR-14-0329"},{"key":"e_1_2_10_15_1","doi-asserted-by":"publisher","DOI":"10.1002\/1878-0261.12369"},{"key":"e_1_2_10_16_1","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-18-0969"},{"key":"e_1_2_10_17_1","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2021.39.15_suppl.9004"},{"key":"e_1_2_10_18_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms25168594"},{"key":"e_1_2_10_19_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jlb.2024.100153"},{"key":"e_1_2_10_20_1","first-page":"1","article-title":"Biomarker identification and pathway analysis by serum metabolomics of lung cancer","volume":"2015","author":"Chen Y","year":"2015","journal-title":"BioMed Res Int"},{"key":"e_1_2_10_21_1","doi-asserted-by":"publisher","DOI":"10.3390\/metabo14040200"},{"key":"e_1_2_10_22_1","doi-asserted-by":"publisher","DOI":"10.1093\/bib\/bbae498"},{"key":"e_1_2_10_23_1","doi-asserted-by":"publisher","DOI":"10.3390\/metabo10050202"},{"key":"e_1_2_10_24_1","doi-asserted-by":"publisher","DOI":"10.3389\/fgene.2024.1425456"},{"key":"e_1_2_10_25_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0010312"},{"key":"e_1_2_10_26_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tranon.2020.100907"},{"key":"e_1_2_10_27_1","first-page":"2125","article-title":"Decision tree\u2010based classifiers for lung cancer diagnosis and subtyping using TCGA miRNA expression data","volume":"18","author":"Sherafatian M","year":"2019","journal-title":"Oncol Lett"},{"key":"e_1_2_10_28_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkw227"},{"key":"e_1_2_10_29_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cels.2020.12.001"},{"key":"e_1_2_10_30_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-021-22989-1"},{"key":"e_1_2_10_31_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.123.3191.309"},{"key":"e_1_2_10_32_1","doi-asserted-by":"publisher","DOI":"10.3389\/fphys.2015.00382"},{"key":"e_1_2_10_33_1","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2105-11-489"},{"key":"e_1_2_10_34_1","doi-asserted-by":"publisher","DOI":"10.1038\/msb.2010.47"},{"key":"e_1_2_10_35_1","doi-asserted-by":"publisher","DOI":"10.1101\/gr.3992505"},{"key":"e_1_2_10_36_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pcbi.1000489"},{"key":"e_1_2_10_37_1","doi-asserted-by":"publisher","DOI":"10.1186\/1752-0509-6-73"},{"key":"e_1_2_10_38_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pcbi.1000082"},{"key":"e_1_2_10_39_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pcbi.1002518"},{"key":"e_1_2_10_40_1","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btq602"},{"key":"e_1_2_10_41_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pcbi.1002662"},{"key":"e_1_2_10_42_1","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btt493"},{"key":"e_1_2_10_43_1","doi-asserted-by":"publisher","DOI":"10.1038\/nbt.4072"},{"key":"e_1_2_10_44_1","doi-asserted-by":"publisher","DOI":"10.1093\/bib\/bbx153"},{"key":"e_1_2_10_45_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-020-72664-6"},{"key":"e_1_2_10_46_1","doi-asserted-by":"publisher","DOI":"10.3390\/genes12091335"},{"key":"e_1_2_10_47_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.critrevonc.2017.02.001"},{"key":"e_1_2_10_48_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkl887"},{"key":"e_1_2_10_49_1","doi-asserted-by":"publisher","DOI":"10.1093\/biostatistics\/4.2.249"},{"key":"e_1_2_10_50_1","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btg405"},{"key":"e_1_2_10_51_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature11003"},{"key":"e_1_2_10_52_1","doi-asserted-by":"publisher","DOI":"10.1186\/s40170-015-0140-6"},{"key":"e_1_2_10_53_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ifacol.2022.09.168"},{"volume-title":"15th international symposium on health informatics and bioinformatics HIBIT\u201922 (20\u201322 October 2022)","year":"2022","author":"K\u0131z\u0131lilsoley N","key":"e_1_2_10_54_1"},{"key":"e_1_2_10_55_1","doi-asserted-by":"publisher","DOI":"10.1007\/978-3-540-45058-0_5"},{"key":"e_1_2_10_56_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tranon.2023.101667"},{"key":"e_1_2_10_57_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12935-024-03276-7"},{"key":"e_1_2_10_58_1","doi-asserted-by":"publisher","DOI":"10.7150\/jca.93890"},{"key":"e_1_2_10_59_1","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.02435-16"},{"key":"e_1_2_10_60_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41392-024-01981-3"},{"key":"e_1_2_10_61_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.aaf5171"},{"key":"e_1_2_10_62_1","doi-asserted-by":"publisher","DOI":"10.31083\/j.fbl2806107"},{"key":"e_1_2_10_63_1","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2024.1389804"},{"key":"e_1_2_10_64_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00109-015-1377-9"},{"key":"e_1_2_10_65_1","doi-asserted-by":"publisher","DOI":"10.1155\/2015\/685303"},{"key":"e_1_2_10_66_1","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2407-9-16"},{"key":"e_1_2_10_67_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41556-023-01241-6"},{"key":"e_1_2_10_68_1","doi-asserted-by":"publisher","DOI":"10.7150\/jca.69583"},{"key":"e_1_2_10_69_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41375-023-02103-8"},{"key":"e_1_2_10_70_1","doi-asserted-by":"publisher","DOI":"10.1042\/EBC20230096"},{"key":"e_1_2_10_71_1","first-page":"1","article-title":"The role of CDC25C in cell cycle regulation and clinical cancer therapy: a systematic review","volume":"20","author":"Liu K","year":"2020","journal-title":"Cancer Cell Int"},{"key":"e_1_2_10_72_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms232214102"},{"key":"e_1_2_10_73_1","doi-asserted-by":"publisher","DOI":"10.3390\/biom15010003"},{"key":"e_1_2_10_74_1","doi-asserted-by":"crossref","unstructured":"DengY ZhangX LiD XuH.Pan\u2010cancer analysis of the oncogenic effect of SorCS1 in human tumors and its correlation with LRP2 protein. 2022. Preprint at Research Square:10.21203\/rs.3.rs-2186632\/v1","DOI":"10.21203\/rs.3.rs-2186632\/v1"},{"key":"e_1_2_10_75_1","doi-asserted-by":"publisher","DOI":"10.3892\/or.2024.8776"},{"key":"e_1_2_10_76_1","doi-asserted-by":"publisher","DOI":"10.3389\/fcell.2021.647387"},{"key":"e_1_2_10_77_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0052555"},{"key":"e_1_2_10_78_1","doi-asserted-by":"publisher","DOI":"10.1186\/s43066-023-00308-1"},{"key":"e_1_2_10_79_1","doi-asserted-by":"publisher","DOI":"10.3390\/biomedicines9111601"},{"key":"e_1_2_10_80_1","doi-asserted-by":"publisher","DOI":"10.1093\/glycob\/cwad070"},{"key":"e_1_2_10_81_1","doi-asserted-by":"publisher","DOI":"10.3892\/or.2020.7803"},{"key":"e_1_2_10_82_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10555-023-10164-5"},{"key":"e_1_2_10_83_1","first-page":"1","article-title":"Prognostic biomarker MICAL2 and\u00a0associates with proliferation, migration and immune infiltration in pancreatic adenocarcinoma","author":"Yang H","year":"2024","journal-title":"J Appl Genet"},{"key":"e_1_2_10_84_1","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-24-0744"},{"key":"e_1_2_10_85_1","doi-asserted-by":"publisher","DOI":"10.1007\/s12672-024-01244-1"},{"key":"e_1_2_10_86_1","doi-asserted-by":"publisher","DOI":"10.1093\/carcin\/bgab011"},{"key":"e_1_2_10_87_1","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2022.949863"},{"key":"e_1_2_10_88_1","doi-asserted-by":"publisher","DOI":"10.1242\/jcs.020248"},{"key":"e_1_2_10_89_1","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2022.870721"},{"key":"e_1_2_10_90_1","doi-asserted-by":"publisher","DOI":"10.7150\/jca.79236"},{"key":"e_1_2_10_91_1","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2020.595498"},{"key":"e_1_2_10_92_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13046-024-02994-0"},{"key":"e_1_2_10_93_1","doi-asserted-by":"publisher","DOI":"10.1002\/9781119000822.hfcm002.pub2"},{"key":"e_1_2_10_94_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0157101"},{"key":"e_1_2_10_95_1","doi-asserted-by":"publisher","DOI":"10.1006\/mben.2001.0188"},{"key":"e_1_2_10_96_1","doi-asserted-by":"publisher","DOI":"10.1186\/s40364-017-0082-y"},{"key":"e_1_2_10_97_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12864-024-11112-5"},{"key":"e_1_2_10_98_1","doi-asserted-by":"publisher","DOI":"10.3389\/fphys.2013.00237"},{"key":"e_1_2_10_99_1","doi-asserted-by":"publisher","DOI":"10.3390\/cancers16132302"},{"key":"e_1_2_10_100_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2011.02.013"},{"key":"e_1_2_10_101_1","doi-asserted-by":"publisher","DOI":"10.1186\/s40537-019-0192-5"},{"key":"e_1_2_10_102_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkl995"},{"key":"e_1_2_10_103_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pgen.1005895"},{"key":"e_1_2_10_104_1","doi-asserted-by":"publisher","DOI":"10.1186\/gb-2011-12-4-r41"},{"key":"e_1_2_10_105_1","doi-asserted-by":"publisher","DOI":"10.7171\/jbt.21-3202-001"},{"key":"e_1_2_10_106_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pcbi.1005758"},{"key":"e_1_2_10_107_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymben.2016.10.022"},{"key":"e_1_2_10_108_1","doi-asserted-by":"publisher","DOI":"10.1186\/1752-0509-7-74"},{"key":"e_1_2_10_109_1","doi-asserted-by":"publisher","DOI":"10.1093\/ajcp\/72.1.21"},{"key":"e_1_2_10_110_1","doi-asserted-by":"publisher","DOI":"10.1002\/(SICI)1097-0290(19960505)50:3<299::AID-BIT9>3.0.CO;2-B"},{"key":"e_1_2_10_111_1","doi-asserted-by":"publisher","DOI":"10.1214\/aoms\/1177730491"},{"key":"e_1_2_10_112_1","doi-asserted-by":"publisher","DOI":"10.2307\/3001968"},{"key":"e_1_2_10_113_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.2517-6161.1995.tb02031.x"},{"key":"e_1_2_10_114_1","doi-asserted-by":"publisher","DOI":"10.1007\/978-0-387-77240-0_14"},{"key":"e_1_2_10_115_1","first-page":"2825","article-title":"Scikit\u2010learn: machine learning in Python","volume":"12","author":"Pedregosa F","year":"2011","journal-title":"J Mach Learn Res"},{"key":"e_1_2_10_116_1","doi-asserted-by":"publisher","DOI":"10.1109\/SIBGRAPI51738.2020.00053"},{"key":"e_1_2_10_117_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkh036"},{"issue":"3","key":"e_1_2_10_118_1","article-title":"clusterProfiler 4.0: a universal enrichment tool for interpreting omics data","volume":"2","author":"Wu T","year":"2021","journal-title":"Innovation"}],"container-title":["Quantitative Biology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/qub2.70012","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,9,20]],"date-time":"2025-09-20T04:55:07Z","timestamp":1758344107000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/qub2.70012"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,8,5]]},"references-count":117,"journal-issue":{"issue":"4","published-print":{"date-parts":[[2025,12]]}},"alternative-id":["10.1002\/qub2.70012"],"URL":"https:\/\/doi.org\/10.1002\/qub2.70012","archive":["Portico"],"relation":{},"ISSN":["2095-4689","2095-4697"],"issn-type":[{"type":"print","value":"2095-4689"},{"type":"electronic","value":"2095-4697"}],"subject":[],"published":{"date-parts":[[2025,8,5]]},"assertion":[{"value":"2025-01-15","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-05-13","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-08-05","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e70012"}}