{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,27]],"date-time":"2026-04-27T12:45:32Z","timestamp":1777293932834,"version":"3.51.4"},"reference-count":109,"publisher":"Public Library of Science (PLoS)","issue":"9","license":[{"start":{"date-parts":[[2023,9,15]],"date-time":"2023-09-15T00:00:00Z","timestamp":1694736000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000289","name":"Cancer Research UK","doi-asserted-by":"publisher","award":["C42109\/A26982 and C42109\/A24747"],"award-info":[{"award-number":["C42109\/A26982 and C42109\/A24747"]}],"id":[{"id":"10.13039\/501100000289","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100014013","name":"UK Research and Innovation","doi-asserted-by":"publisher","award":["MR\/T043571\/1"],"award-info":[{"award-number":["MR\/T043571\/1"]}],"id":[{"id":"10.13039\/100014013","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.ploscompbiol.org"],"crossmark-restriction":false},"short-container-title":["PLoS Comput Biol"],"abstract":"<jats:p>It is increasingly apparent that cancer cells, in addition to remodelling their metabolism to survive and proliferate, adapt and manipulate the metabolism of other cells. This property may be a telling sign that pre-clinical tumour metabolism studies exclusively utilising <jats:italic>in-vitro<\/jats:italic> mono-culture models could prove to be limited for uncovering novel metabolic targets able to translate into clinical therapies. Although this is increasingly recognised, and work towards addressing the issue is becoming routinary much remains poorly understood. For instance, knowledge regarding the biochemical mechanisms through which cancer cells manipulate non-cancerous cell metabolism, and the subsequent impact on their survival and proliferation remains limited. Additionally, the variations in these processes across different cancer types and progression stages, and their implications for therapy, also remain largely unexplored. This study employs an interdisciplinary approach that leverages the predictive power of mathematical modelling to enrich experimental findings. We develop a functional multicellular <jats:italic>in-silico<\/jats:italic> model that facilitates the qualitative and quantitative analysis of the metabolic network spawned by an <jats:italic>in-vitro<\/jats:italic> co-culture model of bone marrow mesenchymal stem- and myeloma cell lines. To procure this model, we devised a bespoke human genome constraint-based reconstruction workflow that combines aspects from the legacy mCADRE &amp; Metabotools algorithms, the novel redHuman algorithm, along with <jats:sup>13<\/jats:sup>C-metabolic flux analysis. Our workflow transforms the latest human metabolic network matrix (Recon3D) into two cell-specific models coupled with a metabolic network spanning a shared growth medium. When cross-validating our <jats:italic>in-silico<\/jats:italic> model against the in-vitro model, we found that the <jats:italic>in-silico<\/jats:italic> model successfully reproduces vital metabolic behaviours of its <jats:italic>in-vitro<\/jats:italic> counterpart; results include cell growth predictions, respiration rates, as well as support for observations which suggest cross-shuttling of redox-active metabolites between cells.<\/jats:p>","DOI":"10.1371\/journal.pcbi.1011374","type":"journal-article","created":{"date-parts":[[2023,9,15]],"date-time":"2023-09-15T20:03:48Z","timestamp":1694808228000},"page":"e1011374","update-policy":"https:\/\/doi.org\/10.1371\/journal.pcbi.corrections_policy","source":"Crossref","is-referenced-by-count":5,"title":["Mathematical reconstruction of the metabolic network in an in-vitro multiple myeloma model"],"prefix":"10.1371","volume":"19","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4090-3557","authenticated-orcid":true,"given":"Elias","family":"Vera-Siguenza","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Cristina","family":"Escribano-Gonzalez","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Irene","family":"Serrano-Gonzalo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kattri-Liis","family":"Eskla","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fabian","family":"Spill","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0499-2732","authenticated-orcid":true,"given":"Daniel","family":"Tennant","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"340","published-online":{"date-parts":[[2023,9,15]]},"reference":[{"issue":"3","key":"pcbi.1011374.ref001","doi-asserted-by":"crossref","first-page":"246","DOI":"10.1002\/bies.200900145","article-title":"When metabolism meets topology: Reconciling metabolite and reaction networks","volume":"32","author":"R Montanez","year":"2010","journal-title":"Bioessays"},{"key":"pcbi.1011374.ref002","volume-title":"Metabolism at a Glance","author":"JG Salway","year":"2016"},{"issue":"9","key":"pcbi.1011374.ref003","doi-asserted-by":"crossref","first-page":"877","DOI":"10.1101\/gad.189365.112","article-title":"Links between metabolism and cancer","volume":"26","author":"CV Dang","year":"2012","journal-title":"Genes Dev"},{"issue":"10","key":"pcbi.1011374.ref004","doi-asserted-by":"crossref","first-page":"103110","DOI":"10.1016\/j.isci.2021.103110","article-title":"Importance of the biomass formulation for cancer metabolic modeling and drug prediction","volume":"24","author":"M. 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