{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,23]],"date-time":"2025-10-23T16:40:42Z","timestamp":1761237642768},"reference-count":53,"publisher":"Oxford University Press (OUP)","issue":"18","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2009,9,15]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>We present a multiscale agent-based non-small cell lung cancer model that consists of a 3D environment with which cancer cells interact while processing phenotypic changes. At the molecular level, transforming growth factor \u03b2 (TGF\u03b2) has been integrated into our previously developed in silico model as a second extrinsic input in addition to epidermal growth factor (EGF). The main aim of this study is to investigate how the effects of individual and combinatorial change in EGF and TGF\u03b2 concentrations at the molecular level alter tumor growth dynamics on the multi-cellular level, specifically tumor volume and expansion rate. Our simulation results show that separate EGF and TGF\u03b2 fluctuations trigger competing multi-cellular phenotypes, yet synchronous EGF and TGF\u03b2 signaling yields a spatially more aggressive tumor that overall exhibits an EGF-driven phenotype. By altering EGF and TGF\u03b2 concentration levels simultaneously and asynchronously, we discovered a particular region of EGF-TGF\u03b2 profiles that ensures phenotypic stability of the tumor system. Within this region, concentration changes in EGF and TGF\u03b2 do not impact the resulting multi-cellular response substantially, while outside these concentration ranges, a change at the molecular level will substantially alter either tumor volume or tumor expansion rate, or both. By evaluating tumor growth dynamics across different scales, we show that, under certain conditions, therapeutic targeting of only one signaling pathway may be insufficient. Potential implications of these in silico results for future clinico-pharmacological applications are discussed.<\/jats:p>\n               <jats:p>Contact: \u00a0deisboec@helix.mgh.harvard.edu<\/jats:p>\n               <jats:p>Supplementary information: \u00a0Supplementary data are available at Bioinformatics online.<\/jats:p>","DOI":"10.1093\/bioinformatics\/btp416","type":"journal-article","created":{"date-parts":[[2009,7,5]],"date-time":"2009-07-05T00:13:38Z","timestamp":1246752818000},"page":"2389-2396","source":"Crossref","is-referenced-by-count":60,"title":["Cross-scale, cross-pathway evaluation using an agent-based non-small cell lung cancer model"],"prefix":"10.1093","volume":"25","author":[{"given":"Zhihui","family":"Wang","sequence":"first","affiliation":[{"name":"1 Harvard-MIT (HST) Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Charlestown, MA 02129 and 2Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA"}]},{"given":"Christina M.","family":"Birch","sequence":"additional","affiliation":[{"name":"1 Harvard-MIT (HST) Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Charlestown, MA 02129 and 2Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA"}]},{"given":"Jonathan","family":"Sagotsky","sequence":"additional","affiliation":[{"name":"1 Harvard-MIT (HST) Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Charlestown, MA 02129 and 2Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA"}]},{"given":"Thomas S.","family":"Deisboeck","sequence":"additional","affiliation":[{"name":"1 Harvard-MIT (HST) Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Charlestown, MA 02129 and 2Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA"}]}],"member":"286","published-online":{"date-parts":[[2009,7,4]]},"reference":[{"key":"2023013112120971500_B1","doi-asserted-by":"crossref","first-page":"4446s","DOI":"10.1158\/1078-0432.CCR-06-0623","article-title":"Novel combinations based on epidermal growth factor receptor inhibition","volume":"12","author":"Adjei","year":"2006","journal-title":"Clin. 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