{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T19:43:03Z","timestamp":1792093383449,"version":"4.4.0"},"reference-count":33,"publisher":"MDPI AG","issue":"15","license":[{"start":{"date-parts":[[2025,7,30]],"date-time":"2025-07-30T00:00:00Z","timestamp":1753833600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Science and Technology Council, Taiwan","award":["NSTC112-2321-B-030-001"],"award-info":[{"award-number":["NSTC112-2321-B-030-001"]}]},{"name":"National Science and Technology Council, Taiwan","award":["NSTC113-2221-E-194-001"],"award-info":[{"award-number":["NSTC113-2221-E-194-001"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>Pancreatic cancer is frequently accompanied by cancer-associated cachexia, a debilitating metabolic syndrome marked by progressive skeletal muscle wasting and systemic metabolic dysfunction. This study presents a systems biology framework to simultaneously identify therapeutic targets for both pancreatic ductal adenocarcinoma (PDAC) and its associated cachexia (PDAC-CX), using cell-specific genome-scale metabolic models (GSMMs). The human metabolic network Recon3D was extended to include protein synthesis, degradation, and recycling pathways for key inflammatory and structural proteins. These enhancements enabled the reconstruction of cell-specific GSMMs for PDAC and PDAC-CX, and their respective healthy counterparts, based on transcriptomic datasets. Medium-independent metabolic biomarkers were identified through Parsimonious Metabolite Flow Variability Analysis and differential expression analysis across five nutritional conditions. A fuzzy multi-objective optimization framework was employed within the anticancer target discovery platform to evaluate cell viability and metabolic deviation as dual criteria for assessing therapeutic efficacy and potential side effects. While single-enzyme targets were found to be context-specific and medium-dependent, eight combinatorial targets demonstrated robust, medium-independent effects in both PDAC and PDAC-CX cells. These include the knockout of SLC29A2, SGMS1, CRLS1, and the RNF20\u2013RNF40 complex, alongside upregulation of CERK and PIKFYVE. The proposed integrative strategy offers novel therapeutic avenues that address both tumor progression and cancer-associated cachexia, with improved specificity and reduced off-target effects, thereby contributing to translational oncology.<\/jats:p>","DOI":"10.3390\/molecules30153200","type":"journal-article","created":{"date-parts":[[2025,7,30]],"date-time":"2025-07-30T14:00:41Z","timestamp":1753884041000},"page":"3200","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Identification of Anticancer Target Combinations to Treat Pancreatic Cancer and Its Associated Cachexia Using Constraint-Based Modeling"],"prefix":"10.3390","volume":"30","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5266-2346","authenticated-orcid":false,"given":"Feng-Sheng","family":"Wang","sequence":"first","affiliation":[{"name":"Department of Chemical Engineering, National Chung Cheng University, Chiayi 621301, Taiwan"},{"name":"Research Center for Systems Biology and Tissue Engineering, National Chung Cheng University, Chiayi 621301, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ching-Kai","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Chemical Engineering, National Chung Cheng University, Chiayi 621301, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7676-0813","authenticated-orcid":false,"given":"Kuang-Tse","family":"Huang","sequence":"additional","affiliation":[{"name":"Department of Chemical Engineering, National Chung Cheng University, Chiayi 621301, Taiwan"},{"name":"Research Center for Systems Biology and Tissue Engineering, National Chung Cheng University, Chiayi 621301, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,7,30]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"657","DOI":"10.1016\/j.cell.2016.12.039","article-title":"Understanding the intersections between metabolism and cancer biology","volume":"168","author":"DeBerardinis","year":"2017","journal-title":"Cell"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1016\/j.cmet.2015.12.006","article-title":"The emerging hallmarks of cancer metabolism","volume":"23","author":"Pavlova","year":"2016","journal-title":"Cell Metab."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"e1600200","DOI":"10.1126\/sciadv.1600200","article-title":"Fundamentals of cancer metabolism","volume":"2","author":"DeBerardinis","year":"2016","journal-title":"Sci. Adv."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"355","DOI":"10.1016\/j.cmet.2022.01.007","article-title":"The hallmarks of cancer metabolism: Still emerging","volume":"34","author":"Pavlova","year":"2022","journal-title":"Cell Metab."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1038\/s12276-018-0027-z","article-title":"Recent advances in cancer metabolism: A technological perspective","volume":"50","author":"Kang","year":"2018","journal-title":"Exp. Mol. Med."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"489","DOI":"10.1016\/S1470-2045(10)70218-7","article-title":"Definition and classification of cancer cachexia: An international consensus","volume":"12","author":"Fearon","year":"2011","journal-title":"Lancet Oncol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1333","DOI":"10.1038\/nm1677","article-title":"Tumor-induced anorexia and weight loss are mediated by the TGF-beta superfamily cytokine MIC-1","volume":"13","author":"Johnen","year":"2007","journal-title":"Nat. Med."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1264","DOI":"10.1038\/s41591-020-0945-x","article-title":"Antibody-mediated inhibition of GDF15\u2013GFRAL activity reverses cancer cachexia in mice","volume":"26","author":"Suriben","year":"2020","journal-title":"Nat. Med."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"331","DOI":"10.1016\/j.cmet.2020.08.003","article-title":"An antibody attack against body wasting in cancer","volume":"32","author":"Rohm","year":"2020","journal-title":"Cell Metab."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Bonetto, A., Aydogdu, T., Kunzevitzky, N., Guttridge, D.C., Khuri, S., Koniaris, L.G., Zimmers, T.A., and Parise, G. (2011). STAT3 activation in skeletal muscle links muscle wasting and the acute phase response in cancer cachexia. PLoS ONE, 6.","DOI":"10.1371\/journal.pone.0022538"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1612","DOI":"10.1016\/j.celrep.2019.07.016","article-title":"Modeling human cancer-induced cachexia","volume":"28","author":"Talbert","year":"2019","journal-title":"Cell Rep."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"162","DOI":"10.1038\/s41420-022-00972-z","article-title":"GDF-15 in tumor-derived exosomes promotes muscle atrophy via Bcl-2\/caspase-3 pathway","volume":"8","author":"Zhang","year":"2022","journal-title":"Cell Death Discov."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"219","DOI":"10.1136\/thoraxjnl-2014-206225","article-title":"Increased expression of GDF-15 may mediate ICU-acquired weakness by down-regulating muscle microRNAs","volume":"70","author":"Bloch","year":"2015","journal-title":"Thorax"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"164","DOI":"10.1136\/thoraxjnl-2017-211440","article-title":"Growth\/differentiation factor 15 causes TGF\u03b2-activated kinase 1-dependent muscle atrophy in pulmonary arterial hypertension","volume":"74","author":"Garfield","year":"2019","journal-title":"Thorax"},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Cheng, C.T., Wang, T.Y., Chen, P.R., Wu, W.H., Lai, J.M., Sawiak, S., Moore, S., Parfitt, L., Harries, C., and Rice, M. (2021). Computer-aided design for identifying anticancer targets in genome-scale metabolic models of colon cancer. Biology, 10.","DOI":"10.3390\/biology10111115"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"2078","DOI":"10.1002\/2211-5463.13231","article-title":"Optimization of a modeling platform to predict oncogenes from genome-scale metabolic networks of non-small-cell lung cancers","volume":"11","author":"Wang","year":"2021","journal-title":"FEBS Openbio"},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Wang, F.S., and Zhang, H.X. (2024). Identification of anticancer enzymes and biomarkers for hepatocellular carcinoma through constraint-based modeling. Molecules, 29.","DOI":"10.21203\/rs.3.rs-4007352\/v1"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"272","DOI":"10.1038\/nbt.4072","article-title":"Recon3D enables a three-dimensional view of gene variation in human metabolism","volume":"36","author":"Brunk","year":"2018","journal-title":"Nat. Biotechnol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1198","DOI":"10.1093\/carcin\/bgac092","article-title":"Dysregulation of HNF1B\/Clusterin axis enhances disease progression in a highly aggressive subset of pancreatic cancer patients","volume":"43","author":"Yang","year":"2022","journal-title":"Carcinogenesis"},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Narasimhan, A., Zhong, X., Au, E.P., Ceppa, E.P., Nakeeb, A., House, M.G., Zyromski, N.J., Schmidt, C.M., Schloss, K.N.H., and Schloss, D.E.I. (2021). Profiling of adipose and skeletal muscle in human pancreatic cancer cachexia reveals distinct gene profiles with convergent pathways. Cancers, 13.","DOI":"10.20944\/preprints202103.0658.v1"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"e14604","DOI":"10.1200\/jco.2011.29.15_suppl.e14604","article-title":"Use of elevated IL-1 to predict prognosis in patients with advanced pancreatic cancer with high IL-6 and wasting condition","volume":"29","author":"Mitsunaga","year":"2011","journal-title":"J. Clin. Oncol."},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Balsano, R., Kruize, Z., Lunardi, M., Comandatore, A., Barone, M., Cavazzoni, A., Cecconi, A.D.R., Morelli, L., Wilmink, H., and Tiseo, M. (2022). Transforming growth factor-beta signaling in cancer-induced cachexia: From molecular pathways to the clinics. Cells, 11.","DOI":"10.3390\/cells11172671"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"120","DOI":"10.1158\/1078-0432.CCR-13-0150","article-title":"Targeting of NAD metabolism in pancreatic cancer cells: Potential novel therapy for pancreatic tumors","volume":"20","author":"Chini","year":"2013","journal-title":"Clin. Cancer Res."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Gao, F., Sun, K., Wang, S., Zhang, X., and Ba, X. (2025). Lactate metabolism reprogramming in PDAC: Potential for tumor therapy. Biochim. Biophys. Acta, 1880.","DOI":"10.1016\/j.bbcan.2025.189373"},{"key":"ref_25","first-page":"e74528","article-title":"Metabolite biomarkers for early detection of pancreatic ductal adenocarcinoma: A systematic review","volume":"16","author":"Rehman","year":"2024","journal-title":"Cureus"},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Zhao, R., Chen, S., Cui, W., Xie, C., and Zhang, A. (2023). PTPN1 is a prognostic biomarker related to cancer immunity and drug sensitivity: From pan-cancer analysis to validation in breast cancer. Front. Immunol., 14.","DOI":"10.3389\/fimmu.2023.1232047"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"E363","DOI":"10.1152\/ajpendo.00487.2002","article-title":"Glucocorticoid-induced skeletal muscle atrophy is associated with upregulation of myostatin gene expression","volume":"5","author":"Ma","year":"2003","journal-title":"Am. J. Physiol. Endocrinol. Metab."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"4323","DOI":"10.1038\/emboj.2011.292","article-title":"C\/EBP\u03b2 mediates tumour-induced ubiquitin ligase atrogin1\/MAFbx upregulation and muscle wasting","volume":"30","author":"Zhang","year":"2011","journal-title":"EMBO J."},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Pierucci, F., Frati, A., Battistini, C., Penna, F., Costelli, P., and Meacci, E. (2021). Control of skeletal muscle atrophy associated to cancer or corticosteroids by ceramide kinase. Cancers, 13.","DOI":"10.3390\/cancers13133285"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"E119","DOI":"10.1152\/ajpendo.00030.2013","article-title":"Muscle-specific Pikfyve gene disruption causes glucose intolerance, insulin resistance, adiposity, and hyperinsulinemia but not muscle fiber-type switching","volume":"305","author":"Ikonomov","year":"2013","journal-title":"Am. J. Physiol. Endocrinol. Metab."},{"key":"ref_31","unstructured":"Haynie, D.T. (2009). Biological Thermodynamics, Cambridge University Press. [2nd ed.]."},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Chu, S.W., and Wang, F.S. (2023). Fuzzy optimization for identifying antiviral targets for treating SARS-CoV-2 infection in the heart. BMC Bioinform., 24.","DOI":"10.1186\/s12859-023-05487-7"},{"key":"ref_33","first-page":"10427","article-title":"Human\/SARS-CoV-2 genome-scale metabolic modeling to discover potential antiviral targets for COVID-19","volume":"133","author":"Wang","year":"2023","journal-title":"J. Taiwan Inst. Chem. Eng."}],"container-title":["Molecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1420-3049\/30\/15\/3200\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T18:19:08Z","timestamp":1760033948000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1420-3049\/30\/15\/3200"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,7,30]]},"references-count":33,"journal-issue":{"issue":"15","published-online":{"date-parts":[[2025,8]]}},"alternative-id":["molecules30153200"],"URL":"https:\/\/doi.org\/10.3390\/molecules30153200","relation":{},"ISSN":["1420-3049"],"issn-type":[{"value":"1420-3049","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,7,30]]}}}