{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,13]],"date-time":"2026-04-13T14:34:10Z","timestamp":1776090850554,"version":"3.50.1"},"update-to":[{"DOI":"10.1371\/journal.pcbi.1010701","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2022,12,13]],"date-time":"2022-12-13T00:00:00Z","timestamp":1670889600000}}],"reference-count":81,"publisher":"Public Library of Science (PLoS)","issue":"11","license":[{"start":{"date-parts":[[2022,11,28]],"date-time":"2022-11-28T00:00:00Z","timestamp":1669593600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000001","name":"National Science Foundation","doi-asserted-by":"publisher","award":["1700687"],"award-info":[{"award-number":["1700687"]}],"id":[{"id":"10.13039\/100000001","id-type":"DOI","asserted-by":"publisher"}]},{"name":"University of Virginia Center for Engineering in Medicine"},{"name":"University of Virginia Center for Advanced Biomanufacturing"},{"DOI":"10.13039\/100000997","name":"Arnold and Mabel Beckman Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000997","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.ploscompbiol.org"],"crossmark-restriction":false},"short-container-title":["PLoS Comput Biol"],"abstract":"<jats:p>Physiological and pathological processes including embryogenesis and tumorigenesis rely on the ability of individual cells to work collectively to form multicell patterns. In these heterogeneous multicell systems, cell-cell signaling induces differential adhesion between cells that leads to tissue-level patterning. However, the sensitivity of pattern formation to changes in the strengths of signaling or cell adhesion processes is not well understood. Prior work has explored these issues using synthetically engineered heterogeneous multicell spheroid systems, in which cell subpopulations engage in bidirectional intercellular signaling to regulate the expression of different cadherins. While engineered cell systems provide excellent experimental tools to observe pattern formation in cell populations, computational models of these systems may be leveraged to explore more systematically how specific combinations of signaling and adhesion parameters can drive the emergence of unique patterns. We developed and validated two- and three-dimensional agent-based models (ABMs) of spheroid patterning for previously described cells engineered with a bidirectional signaling circuit that regulates N- and P-cadherin expression. Systematic exploration of model predictions, some of which were experimentally validated, revealed how cell seeding parameters, the order of signaling events, probabilities of induced cadherin expression, and homotypic adhesion strengths affect pattern formation. Unsupervised clustering was also used to map combinations of signaling and adhesion parameters to these unique spheroid patterns predicted by the ABM. Finally, we demonstrated how the model may be deployed to design new synthetic cell signaling circuits based on a desired final multicell pattern.<\/jats:p>","DOI":"10.1371\/journal.pcbi.1010701","type":"journal-article","created":{"date-parts":[[2022,11,28]],"date-time":"2022-11-28T18:58:34Z","timestamp":1669661914000},"page":"e1010701","update-policy":"https:\/\/doi.org\/10.1371\/journal.pcbi.corrections_policy","source":"Crossref","is-referenced-by-count":9,"title":["A computational modeling approach for predicting multicell spheroid patterns based on signaling-induced differential adhesion"],"prefix":"10.1371","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5140-6188","authenticated-orcid":true,"given":"Nikita","family":"Sivakumar","sequence":"first","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5547-8111","authenticated-orcid":true,"given":"Helen V.","family":"Warner","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5857-5606","authenticated-orcid":true,"given":"Shayn M.","family":"Peirce","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4244-6599","authenticated-orcid":true,"given":"Matthew J.","family":"Lazzara","sequence":"additional","affiliation":[]}],"member":"340","published-online":{"date-parts":[[2022,11,28]]},"reference":[{"issue":"1","key":"pcbi.1010701.ref001","doi-asserted-by":"crossref","first-page":"a008227","DOI":"10.1101\/cshperspect.a008227","article-title":"Molecular mechanisms of cell segregation and boundary formation in development and tumorigenesis","volume":"4","author":"E Batlle","year":"2012","journal-title":"Cold Spring Harb Perspect Biol"},{"issue":"6398","key":"pcbi.1010701.ref002","doi-asserted-by":"crossref","first-page":"156","DOI":"10.1126\/science.aat0271","article-title":"Programming self-organizing multicellular structures with synthetic cell-cell signaling","volume":"361","author":"S Toda","year":"2018","journal-title":"Science"},{"issue":"4","key":"pcbi.1010701.ref003","doi-asserted-by":"crossref","first-page":"395","DOI":"10.1002\/jez.1401730406","article-title":"Does differential adhesion govern self-assembly processes in histogenesis? Equilibrium configurations and the emergence of a hierarchy among populations of embryonic cells","volume":"173","author":"MS Steinberg","year":"1970","journal-title":"J Exp Zool"},{"issue":"3579","key":"pcbi.1010701.ref004","doi-asserted-by":"crossref","first-page":"401","DOI":"10.1126\/science.141.3579.401","article-title":"Reconstruction of tissues by dissociated cells. Some morphogenetic tissue movements and the sorting out of embryonic cells may have a common explanation","volume":"141","author":"MS Steinberg","year":"1963","journal-title":"Science"},{"issue":"1","key":"pcbi.1010701.ref005","doi-asserted-by":"crossref","first-page":"206","DOI":"10.1073\/pnas.91.1.206","article-title":"Experimental specification of cell sorting, tissue spreading, and specific spatial patterning by quantitative differences in cadherin expression","volume":"91","author":"MS Steinberg","year":"1994","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"2","key":"pcbi.1010701.ref006","doi-asserted-by":"crossref","first-page":"309","DOI":"10.1016\/S0012-1606(02)00016-7","article-title":"Cadherin-mediated cell adhesion and tissue segregation: qualitative and quantitative determinants","volume":"253","author":"D Duguay","year":"2003","journal-title":"Dev Biol"},{"issue":"1","key":"pcbi.1010701.ref007","doi-asserted-by":"crossref","first-page":"255","DOI":"10.1016\/j.ydbio.2004.11.012","article-title":"The differential adhesion hypothesis: a direct evaluation","volume":"278","author":"RA Foty","year":"2005","journal-title":"Dev Biol"},{"issue":"3","key":"pcbi.1010701.ref008","first-page":"2128","article-title":"Simulation of the differential adhesion driven rearrangement of biological cells","volume":"47","author":"JA Glazier","year":"1993","journal-title":"Phys Rev E Stat Phys Plasmas Fluids Relat Interdiscip Topics"},{"issue":"10","key":"pcbi.1010701.ref009","doi-asserted-by":"crossref","first-page":"e24999","DOI":"10.1371\/journal.pone.0024999","article-title":"Computer simulations of cell sorting due to differential adhesion","volume":"6","author":"Y Zhang","year":"2011","journal-title":"PLoS One"},{"issue":"4","key":"pcbi.1010701.ref010","doi-asserted-by":"crossref","first-page":"273","DOI":"10.1109\/TCBB.2005.46","article-title":"A framework for three-dimensional simulation of morphogenesis","volume":"2","author":"TM Cickovski","year":"2005","journal-title":"IEEE\/ACM Trans Comput Biol Bioinform"},{"issue":"132","key":"pcbi.1010701.ref011","doi-asserted-by":"crossref","DOI":"10.1098\/rsif.2017.0338","article-title":"Cell segregation and border sharpening by Eph receptor-ephrin-mediated heterotypic repulsion","volume":"14","author":"HB Taylor","year":"2017","journal-title":"J R Soc Interface"},{"issue":"4","key":"pcbi.1010701.ref012","doi-asserted-by":"crossref","first-page":"281","DOI":"10.1016\/j.gde.2007.05.002","article-title":"Differential adhesion in morphogenesis: a modern view","volume":"17","author":"MS Steinberg","year":"2007","journal-title":"Curr Opin Genet Dev"},{"issue":"1","key":"pcbi.1010701.ref013","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1002\/aja.1001940103","article-title":"Expression of cell adhesion molecules during initiation and cessation of neural crest cell migration","volume":"194","author":"T Akitaya","year":"1992","journal-title":"Dev Dyn"},{"issue":"4","key":"pcbi.1010701.ref014","doi-asserted-by":"crossref","first-page":"347","DOI":"10.1016\/S0959-437X(00)00094-0","article-title":"Pattern formation and developmental mechanisms. The cell biological basis of inductive signaling","volume":"10","author":"M Bronner-Fraser","year":"2000","journal-title":"Curr Opin Genet Dev"},{"issue":"2","key":"pcbi.1010701.ref015","doi-asserted-by":"crossref","first-page":"291","DOI":"10.1016\/0012-1606(92)90114-V","article-title":"Effects of antibodies against N-cadherin and N-CAM on the cranial neural crest and neural tube","volume":"153","author":"M Bronner-Fraser","year":"1992","journal-title":"Dev Biol"},{"issue":"23","key":"pcbi.1010701.ref016","doi-asserted-by":"crossref","first-page":"3199","DOI":"10.1101\/gad.1486806","article-title":"Cadherins in development: cell adhesion, sorting, and tissue morphogenesis","volume":"20","author":"JM Halbleib","year":"2006","journal-title":"Genes Dev"},{"key":"pcbi.1010701.ref017","doi-asserted-by":"crossref","first-page":"639","DOI":"10.1242\/dev.102.4.639","article-title":"The cadherins: cell-cell adhesion molecules controlling animal morphogenesis","author":"M. Takeichi","year":"1988","journal-title":"Development"},{"issue":"7","key":"pcbi.1010701.ref018","doi-asserted-by":"crossref","first-page":"993","DOI":"10.1016\/0092-8674(88)90114-6","article-title":"Expressed recombinant cadherins mediate cell sorting in model systems","volume":"54","author":"A Nose","year":"1988","journal-title":"Cell"},{"issue":"1","key":"pcbi.1010701.ref019","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1016\/0092-8674(90)90222-Z","article-title":"Localization of specificity determining sites in cadherin cell adhesion molecules","volume":"61","author":"A Nose","year":"1990","journal-title":"Cell"},{"issue":"3","key":"pcbi.1010701.ref020","first-page":"202","article-title":"Epithelial mesenchymal transition (EMT) in prostate growth and tumor progression","volume":"2","author":"CM Grant","year":"2013","journal-title":"Transl Androl Urol"},{"issue":"3","key":"pcbi.1010701.ref021","doi-asserted-by":"crossref","first-page":"212","DOI":"10.1016\/j.tcb.2018.12.001","article-title":"EMT Transition States during Tumor Progression and Metastasis","volume":"29","author":"I Pastushenko","year":"2019","journal-title":"Trends Cell Biol"},{"issue":"12","key":"pcbi.1010701.ref022","doi-asserted-by":"crossref","first-page":"1469","DOI":"10.1134\/S0006297918120052","article-title":"Role of Epithelial-Mesenchymal Transition in Tumor Progression","volume":"83","author":"NA Gloushankova","year":"2018","journal-title":"Biochemistry (Mosc)"},{"key":"pcbi.1010701.ref023","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1007\/978-1-0716-0779-4_1","article-title":"A Spectrum of Cell States During the Epithelial-to-Mesenchymal Transition","volume":"2179","author":"EJ Hutchins","year":"2021","journal-title":"Methods Mol Biol"},{"issue":"6","key":"pcbi.1010701.ref024","doi-asserted-by":"crossref","first-page":"1438","DOI":"10.1172\/JCI38019","article-title":"Epithelial-mesenchymal transitions: the importance of changing cell state in development and disease","volume":"119","author":"H Acloque","year":"2009","journal-title":"J Clin Invest"},{"issue":"1","key":"pcbi.1010701.ref025","doi-asserted-by":"crossref","first-page":"148","DOI":"10.1073\/pnas.1815345116","article-title":"Toward understanding cancer stem cell heterogeneity in the tumor microenvironment","volume":"116","author":"F Bocci","year":"2019","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"10","key":"pcbi.1010701.ref026","first-page":"3370","article-title":"Zeb1 expression by tumor or stromal cells is associated with spatial distribution patterns of CD8+ tumor-infiltrating lymphocytes: a hypothesis-generating study on 113 triple negative breast cancers","volume":"10","author":"M Ouled Dhaou","year":"2020","journal-title":"Am J Cancer Res"},{"issue":"1","key":"pcbi.1010701.ref027","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1002\/jcb.22545","article-title":"Tissue geometry patterns epithelial-mesenchymal transition via intercellular mechanotransduction","volume":"110","author":"EW Gomez","year":"2010","journal-title":"J Cell Biochem"},{"issue":"1","key":"pcbi.1010701.ref028","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1529\/biophysj.107.114678","article-title":"Modeling the influence of the E-cadherin-beta-catenin pathway in cancer cell invasion: a multiscale approach","volume":"95","author":"I Ramis-Conde","year":"2008","journal-title":"Biophys J"},{"issue":"12","key":"pcbi.1010701.ref029","doi-asserted-by":"crossref","first-page":"1194","DOI":"10.1038\/ncb2122","article-title":"Competition amongst Eph receptors regulates contact inhibition of locomotion and invasiveness in prostate cancer cells","volume":"12","author":"JW Astin","year":"2010","journal-title":"Nat Cell Biol"},{"key":"pcbi.1010701.ref030","doi-asserted-by":"crossref","first-page":"43702","DOI":"10.1038\/srep43702","article-title":"Loss of the EPH receptor B6 contributes to colorectal cancer metastasis","volume":"7","author":"S Mateo-Lozano","year":"2017","journal-title":"Sci Rep"},{"issue":"10","key":"pcbi.1010701.ref031","doi-asserted-by":"crossref","first-page":"1023","DOI":"10.3109\/07357900902769749","article-title":"Cell adhesion molecules: role and clinical significance in cancer","volume":"27","author":"N Makrilia","year":"2009","journal-title":"Cancer Invest"},{"key":"pcbi.1010701.ref032","doi-asserted-by":"crossref","first-page":"85","DOI":"10.3389\/fmed.2018.00085","article-title":"Overview on Clinical Relevance of Intra-Tumor Heterogeneity","volume":"5","author":"G Stanta","year":"2018","journal-title":"Front Med (Lausanne)"},{"issue":"10","key":"pcbi.1010701.ref033","doi-asserted-by":"crossref","first-page":"1219","DOI":"10.1038\/aps.2015.92","article-title":"Intra-tumor heterogeneity of cancer cells and its implications for cancer treatment","volume":"36","author":"XX Sun","year":"2015","journal-title":"Acta Pharmacol Sin"},{"issue":"9","key":"pcbi.1010701.ref034","doi-asserted-by":"crossref","first-page":"1841","DOI":"10.1002\/ijc.30881","article-title":"Spatial distribution of EGFR and KRAS mutation frequencies correlates with histological growth patterns of lung adenocarcinomas","volume":"141","author":"S Dietz","year":"2017","journal-title":"Int J Cancer"},{"key":"pcbi.1010701.ref035","doi-asserted-by":"crossref","first-page":"163","DOI":"10.1016\/j.cobme.2017.10.008","article-title":"Engineering multicellular systems: using synthetic biology to control tissue self-organization","volume":"4","author":"MB Johnson","year":"2017","journal-title":"Curr Opin Biomed Eng"},{"issue":"5","key":"pcbi.1010701.ref036","doi-asserted-by":"crossref","first-page":"264","DOI":"10.1021\/sb400053b","article-title":"Genetically encoded sender-receiver system in 3D mammalian cell culture","volume":"3","author":"A Carvalho","year":"2014","journal-title":"ACS Synth Biol"},{"issue":"4","key":"pcbi.1010701.ref037","doi-asserted-by":"crossref","first-page":"780","DOI":"10.1016\/j.cell.2016.01.012","article-title":"Engineering Customized Cell Sensing and Response Behaviors Using Synthetic Notch Receptors","volume":"164","author":"L Morsut","year":"2016","journal-title":"Cell"},{"key":"pcbi.1010701.ref038","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1016\/j.coisb.2019.02.008","article-title":"Synthetic development: learning to program multicellular self-organization","volume":"14","author":"S Toda","year":"2019","journal-title":"Current Opinion in Systems Biology"},{"key":"pcbi.1010701.ref039","doi-asserted-by":"crossref","first-page":"10243","DOI":"10.1038\/ncomms10243","article-title":"Genetically engineering self-organization of human pluripotent stem cells into a liver bud-like tissue using Gata6","volume":"7","author":"P Guye","year":"2016","journal-title":"Nat Commun"},{"issue":"13","key":"pcbi.1010701.ref040","doi-asserted-by":"crossref","first-page":"1213","DOI":"10.1016\/S0142-9612(99)00014-9","article-title":"Biological surface engineering: a simple system for cell pattern formation","volume":"20","author":"S Zhang","year":"1999","journal-title":"Biomaterials"},{"issue":"6514","key":"pcbi.1010701.ref041","doi-asserted-by":"crossref","first-page":"327","DOI":"10.1126\/science.abc0033","article-title":"Engineering synthetic morphogen systems that can program multicellular patterning","volume":"370","author":"S Toda","year":"2020","journal-title":"Science"},{"key":"pcbi.1010701.ref042","doi-asserted-by":"crossref","first-page":"137","DOI":"10.1146\/annurev-bioeng-071811-150104","article-title":"Multiscale computational models of complex biological systems","volume":"15","author":"J Walpole","year":"2013","journal-title":"Annu Rev Biomed Eng"},{"issue":"11","key":"pcbi.1010701.ref043","doi-asserted-by":"crossref","first-page":"2577","DOI":"10.1242\/dev.129.11.2577","article-title":"Modeling and computational analysis of EGF receptor-mediated cell communication in Drosophila oogenesis","volume":"129","author":"SY Shvartsman","year":"2002","journal-title":"Development"},{"issue":"14","key":"pcbi.1010701.ref044","doi-asserted-by":"crossref","first-page":"R493","DOI":"10.1016\/S0960-9822(02)00967-3","article-title":"Modeling pattern formation: counting to two in the Drosophila egg","volume":"12","author":"N Barkai","year":"2002","journal-title":"Curr Biol"},{"issue":"15","key":"pcbi.1010701.ref045","doi-asserted-by":"crossref","first-page":"6924","DOI":"10.1073\/pnas.0912734107","article-title":"Scaling of morphogen gradients by an expansion-repression integral feedback control","volume":"107","author":"D Ben-Zvi","year":"2010","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"4","key":"pcbi.1010701.ref046","doi-asserted-by":"crossref","first-page":"747","DOI":"10.1039\/C9ME00036D","article-title":"Learning-accelerated discovery of immune-tumour interactions","volume":"4","author":"J Ozik","year":"2019","journal-title":"Mol Syst Des Eng"},{"key":"pcbi.1010701.ref047","doi-asserted-by":"crossref","first-page":"46","DOI":"10.1186\/1752-0509-1-46","article-title":"Multiscale computational analysis of Xenopus laevis morphogenesis reveals key insights of systems-level behavior","volume":"1","author":"SH Robertson","year":"2007","journal-title":"BMC Syst Biol"},{"issue":"4","key":"pcbi.1010701.ref048","doi-asserted-by":"crossref","first-page":"245","DOI":"10.1093\/bib\/bbm024","article-title":"Combining experiments with multi-cell agent-based modeling to study biological tissue patterning","volume":"8","author":"BC Thorne","year":"2007","journal-title":"Brief Bioinform"},{"issue":"4","key":"pcbi.1010701.ref049","doi-asserted-by":"crossref","first-page":"344","DOI":"10.1002\/bdrc.20106","article-title":"Agent-based modeling of multicell morphogenic processes during development","volume":"81","author":"BC Thorne","year":"2007","journal-title":"Birth Defects Res C Embryo Today"},{"issue":"9","key":"pcbi.1010701.ref050","doi-asserted-by":"crossref","first-page":"987","DOI":"10.1039\/C5IB00024F","article-title":"Agent-based model of angiogenesis simulates capillary sprout initiation in multicellular networks","volume":"7","author":"J Walpole","year":"2015","journal-title":"Integr Biol (Camb)"},{"issue":"1","key":"pcbi.1010701.ref051","doi-asserted-by":"crossref","first-page":"210","DOI":"10.1016\/j.ydbio.2004.03.021","article-title":"Multicellular computer simulation of morphogenesis: blastocoel roof thinning and matrix assembly in Xenopus laevis","volume":"271","author":"D Longo","year":"2004","journal-title":"Dev Biol"},{"issue":"7","key":"pcbi.1010701.ref052","doi-asserted-by":"crossref","first-page":"1129","DOI":"10.1093\/bioinformatics\/bth050","article-title":"CompuCell, a multi-model framework for simulation of morphogenesis","volume":"20","author":"JA Izaguirre","year":"2004","journal-title":"Bioinformatics"},{"key":"pcbi.1010701.ref053","doi-asserted-by":"crossref","first-page":"482","DOI":"10.1016\/j.physa.2004.03.089","article-title":"Non-Turing stripes and spots: a novel mechanism for biological cell clustering","volume":"341","author":"W Zeng","year":"2004","journal-title":"Physica A: Statistical Mechanics and its Applications"},{"issue":"1","key":"pcbi.1010701.ref054","doi-asserted-by":"crossref","first-page":"016008","DOI":"10.1088\/1478-3975\/6\/1\/016008","article-title":"Multi-scale modelling of cancer cell intravasation: the role of cadherins in metastasis","volume":"6","author":"I Ramis-Conde","year":"2009","journal-title":"Phys Biol"},{"issue":"220","key":"pcbi.1010701.ref055","doi-asserted-by":"crossref","first-page":"ra31","DOI":"10.1126\/scisignal.2002764","article-title":"Synthetic signal propagation through direct cell-cell interaction","volume":"5","author":"M Matsuda","year":"2012","journal-title":"Sci Signal"},{"issue":"10","key":"pcbi.1010701.ref056","doi-asserted-by":"crossref","first-page":"e109286","DOI":"10.1371\/journal.pone.0109286","article-title":"Computational modeling reveals that a combination of chemotaxis and differential adhesion leads to robust cell sorting during tissue patterning","volume":"9","author":"RZ Tan","year":"2014","journal-title":"PLoS One"},{"issue":"7","key":"pcbi.1010701.ref057","doi-asserted-by":"crossref","first-page":"1188","DOI":"10.1093\/bioinformatics\/bty766","article-title":"PhysiBoSS: a multi-scale agent-based modelling framework integrating physical dimension and cell signalling","volume":"35","author":"G Letort","year":"2019","journal-title":"Bioinformatics"},{"issue":"2213","key":"pcbi.1010701.ref058","first-page":"20200272","article-title":"Turing pattern design principles and their robustness","volume":"379","author":"ST Vittadello","year":"2021","journal-title":"Philos Trans A Math Phys Eng Sci"},{"issue":"4","key":"pcbi.1010701.ref059","doi-asserted-by":"crossref","first-page":"487","DOI":"10.1098\/rsfs.2011.0113","article-title":"Turing\u2019s model for biological pattern formation and the robustness problem","volume":"2","author":"PK Maini","year":"2012","journal-title":"Interface Focus"},{"issue":"3","key":"pcbi.1010701.ref060","doi-asserted-by":"crossref","first-page":"243","DOI":"10.1016\/j.cels.2019.07.007","article-title":"A Comprehensive Network Atlas Reveals That Turing Patterns Are Common but Not Robust","volume":"9","author":"NS Scholes","year":"2019","journal-title":"Cell Syst"},{"issue":"1\u20132","key":"pcbi.1010701.ref061","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1016\/S0092-8240(05)80008-4","article-title":"The chemical basis of morphogenesis. 1953","volume":"52","author":"AM Turing","year":"1990","journal-title":"Bull Math Biol"},{"key":"pcbi.1010701.ref062","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1016\/j.cobme.2019.12.014","article-title":"Computational modeling of organoid development","volume":"13","author":"DA Norfleet","year":"2020","journal-title":"Current Opinion in Biomedical Engineering"},{"issue":"7037","key":"pcbi.1010701.ref063","doi-asserted-by":"crossref","first-page":"1130","DOI":"10.1038\/nature03461","article-title":"A synthetic multicellular system for programmed pattern formation","volume":"434","author":"S Basu","year":"2005","journal-title":"Nature"},{"issue":"26","key":"pcbi.1010701.ref064","doi-asserted-by":"crossref","first-page":"6572","DOI":"10.1073\/pnas.1720770115","article-title":"Stochastic Turing patterns in a synthetic bacterial population","volume":"115","author":"D Karig","year":"2018","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"1\u20132","key":"pcbi.1010701.ref065","doi-asserted-by":"crossref","first-page":"349","DOI":"10.1016\/j.cell.2011.11.025","article-title":"EMT and dissemination precede pancreatic tumor formation","volume":"148","author":"AD Rhim","year":"2012","journal-title":"Cell"},{"issue":"1","key":"pcbi.1010701.ref066","doi-asserted-by":"crossref","first-page":"309","DOI":"10.1158\/0008-5472.CAN-12-4721","article-title":"ERK1\/2 blockade prevents epithelial-mesenchymal transition in lung cancer cells and promotes their sensitivity to EGFR inhibition","volume":"74","author":"JM Buonato","year":"2014","journal-title":"Cancer Res"},{"key":"pcbi.1010701.ref067","first-page":"11","article-title":"Multiscale computational models of cancer","author":"VH Warner","year":"2019","journal-title":"Current Opinion in Biomedical Engineering"},{"issue":"7","key":"pcbi.1010701.ref068","doi-asserted-by":"crossref","first-page":"e68680","DOI":"10.1371\/journal.pone.0068680","article-title":"Multi-scale modeling predicts a balance of tumor necrosis factor-alpha and interleukin-10 controls the granuloma environment during Mycobacterium tuberculosis infection","volume":"8","author":"NA Cilfone","year":"2013","journal-title":"PLoS One"},{"issue":"5","key":"pcbi.1010701.ref069","doi-asserted-by":"crossref","first-page":"1650","DOI":"10.1128\/IAI.01438-15","article-title":"Multiscale Model of Mycobacterium tuberculosis Infection Maps Metabolite and Gene Perturbations to Granuloma Sterilization Predictions","volume":"84","author":"E Pienaar","year":"2016","journal-title":"Infect Immun"},{"key":"pcbi.1010701.ref070","doi-asserted-by":"crossref","first-page":"183","DOI":"10.3389\/fphar.2016.00183","article-title":"Computational Modeling Predicts Simultaneous Targeting of Fibroblasts and Epithelial Cells Is Necessary for Treatment of Pulmonary Fibrosis","volume":"7","author":"HC Warsinske","year":"2016","journal-title":"Front Pharmacol"},{"key":"pcbi.1010701.ref071","doi-asserted-by":"crossref","first-page":"1481","DOI":"10.3389\/fphys.2019.01481","article-title":"Multiscale Coupling of an Agent-Based Model of Tissue Fibrosis and a Logic-Based Model of Intracellular Signaling","volume":"10","author":"SM Rikard","year":"2019","journal-title":"Front Physiol"},{"key":"pcbi.1010701.ref072","first-page":"28","article-title":"Mechanistic and data-driven models of cell signaling: Tools for fundamental discovery and rational design of therapy","author":"P. J. Myers SHL","year":"2021","journal-title":"Current Opinion in Systems Biology"},{"key":"pcbi.1010701.ref073","doi-asserted-by":"crossref","first-page":"110125","DOI":"10.1016\/j.jtbi.2019.110125","article-title":"Data-driven analysis of a mechanistic model of CAR T cell signaling predicts effects of cell-to-cell heterogeneity","volume":"489","author":"CG Cess","year":"2020","journal-title":"J Theor Biol"},{"issue":"12","key":"pcbi.1010701.ref074","doi-asserted-by":"crossref","first-page":"e1008519","DOI":"10.1371\/journal.pcbi.1008519","article-title":"Multi-scale modeling of macrophage-T cell interactions within the tumor microenvironment","volume":"16","author":"CG Cess","year":"2020","journal-title":"PLoS Comput Biol"},{"issue":"5","key":"pcbi.1010701.ref075","doi-asserted-by":"crossref","first-page":"1297","DOI":"10.1007\/s10237-019-01145-1","article-title":"Spatial scaling in multiscale models: methods for coupling agent-based and finite-element models of wound healing","volume":"18","author":"JJ Lee","year":"2019","journal-title":"Biomech Model Mechanobiol"},{"issue":"5","key":"pcbi.1010701.ref076","doi-asserted-by":"crossref","first-page":"1424","DOI":"10.1152\/japplphysiol.00379.2018","article-title":"Agent-based model illustrates the role of the microenvironment in regeneration in healthy and mdx skeletal muscle","volume":"125","author":"KM Virgilio","year":"2018","journal-title":"J Appl Physiol1985)"},{"issue":"10","key":"pcbi.1010701.ref077","doi-asserted-by":"crossref","DOI":"10.1093\/gigascience\/giz127","article-title":"Key challenges facing data-driven multicellular systems biology","volume":"8","author":"P. Macklin","year":"2019","journal-title":"Gigascience"},{"key":"pcbi.1010701.ref078","doi-asserted-by":"crossref","first-page":"122","DOI":"10.1016\/j.jtbi.2012.02.002","article-title":"Patient-calibrated agent-based modelling of ductal carcinoma in situ (DCIS): from microscopic measurements to macroscopic predictions of clinical progression","volume":"301","author":"P Macklin","year":"2012","journal-title":"J Theor Biol"},{"key":"pcbi.1010701.ref079","volume-title":"Center for Connected Learning and Computer-Based Modeling","author":"Northwestern University","year":"1999"},{"key":"pcbi.1010701.ref080","article-title":"NL4Py: Agent-Based Modeling in Python with Parallelizable NetLogo Workspaces","author":"C Gunaratne","year":"2018"},{"issue":"85","key":"pcbi.1010701.ref081","first-page":"2825","article-title":"Scikit-learn: Machine Learning in Python","volume":"12","author":"F Pedregosa","year":"2021","journal-title":"Journal of Machine Learning Research"}],"updated-by":[{"DOI":"10.1371\/journal.pcbi.1011166","type":"correction","label":"Correction","source":"publisher","updated":{"date-parts":[[2023,5,22]],"date-time":"2023-05-22T00:00:00Z","timestamp":1684713600000}},{"DOI":"10.1371\/journal.pcbi.1010701","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2022,12,13]],"date-time":"2022-12-13T00:00:00Z","timestamp":1670889600000}}],"container-title":["PLOS Computational Biology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pcbi.1010701","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,12,2]],"date-time":"2023-12-02T03:07:52Z","timestamp":1701486472000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pcbi.1010701"}},"subtitle":[],"editor":[{"given":"Philip K.","family":"Maini","sequence":"first","affiliation":[]}],"short-title":[],"issued":{"date-parts":[[2022,11,28]]},"references-count":81,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2022,11,28]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pcbi.1010701","relation":{"correction":[{"id-type":"doi","id":"10.1371\/journal.pcbi.1011166","asserted-by":"object"}],"new_version":[{"id-type":"doi","id":"10.1371\/journal.pcbi.1010701","asserted-by":"object"}]},"ISSN":["1553-7358"],"issn-type":[{"value":"1553-7358","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,11,28]]}}}