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Partial EMT states have been linked to metastatic dissemination and drug resistance. Several interconnected feedback loops at the RNA and protein levels control the transition between different cellular states. Using a combination of mathematical modeling and experimental analyses in the TGF\u03b2-responsive breast epithelial MCF10A cell model, we identify a central role for the tumor suppressor protein Deleted in Liver Cancer 1 (DLC1) during EMT. By extending a previous model of EMT comprising key transcription factors and microRNAs, our work shows that DLC1 acts as a positive regulator of TGF\u03b2-driven EMT, mainly by promoting SNAIL1 expression. Our model predictions indicate that DLC1 loss impairs EMT progression. Experimental analyses confirm this prediction and reveal the acquisition of a partial EMT phenotype in DLC1-depleted cells. Furthermore, our model results indicate a possible EMT reversion to partial or epithelial states upon DLC1 loss in MCF10A cells induced toward mesenchymal phenotypes. The increased EMT plasticity of cells lacking DLC1 may explain its importance as a tumor suppressor.<\/jats:p>","DOI":"10.1371\/journal.pcbi.1013076","type":"journal-article","created":{"date-parts":[[2025,5,12]],"date-time":"2025-05-12T14:03:58Z","timestamp":1747058638000},"page":"e1013076","update-policy":"https:\/\/doi.org\/10.1371\/journal.pcbi.corrections_policy","source":"Crossref","is-referenced-by-count":0,"title":["Integrated mathematical and experimental modeling uncovers enhanced EMT plasticity upon loss of the DLC1 tumor 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defines an anoikis-resistant and spheroidogenic intermediate mesenchymal state that is sensitive to e-cadherin restoration by a src-kinase inhibitor, saracatinib (AZD0530)","volume":"4","author":"RY-J Huang","year":"2013","journal-title":"Cell Death Dis"},{"issue":"45","key":"pcbi.1013076.ref020","doi-asserted-by":"crossref","first-page":"18144","DOI":"10.1073\/pnas.1318192110","article-title":"MicroRNA-based regulation of epithelial-hybrid-mesenchymal fate determination","volume":"110","author":"M Lu","year":"2013","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"17","key":"pcbi.1013076.ref021","doi-asserted-by":"crossref","first-page":"2865","DOI":"10.4161\/cc.10.17.17188","article-title":"Tracking the intermediate stages of epithelial-mesenchymal transition in epithelial stem cells and cancer","volume":"10","author":"NV Jordan","year":"2011","journal-title":"Cell 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Ko","year":"2010","journal-title":"Gastroenterology"},{"key":"pcbi.1013076.ref034","doi-asserted-by":"crossref","first-page":"1618","DOI":"10.1038\/ncomms2604","article-title":"PKA-induced dimerization of the RhoGAP DLC1 promotes its inhibition of tumorigenesis and metastasis","volume":"4","author":"FCF Ko","year":"2013","journal-title":"Nat Commun"},{"issue":"12","key":"pcbi.1013076.ref035","doi-asserted-by":"crossref","first-page":"6686","DOI":"10.1073\/pnas.111614398","article-title":"Genetic programs of epithelial cell plasticity directed by transforming growth factor-beta","volume":"98","author":"J Zavadil","year":"2001","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"10","key":"pcbi.1013076.ref036","doi-asserted-by":"crossref","DOI":"10.26508\/lsa.202101330","article-title":"ERK-Smurf1-RhoA signaling is critical for TGF\u03b2-drived EMT and tumor metastasis","volume":"5","author":"J Zheng","year":"2022","journal-title":"Life Sci Alliance"},{"issue":"19","key":"pcbi.1013076.ref037","doi-asserted-by":"crossref","first-page":"27067","DOI":"10.18632\/oncotarget.8166","article-title":"Stability of the hybrid epithelial\/mesenchymal phenotype","volume":"7","author":"MK Jolly","year":"2016","journal-title":"Oncotarget"},{"issue":"3","key":"pcbi.1013076.ref038","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pcbi.1007682","article-title":"A plausible accelerating function of intermediate states in cancer metastasis","volume":"16","author":"H Goetz","year":"2020","journal-title":"PLoS Comput Biol"},{"issue":"18","key":"pcbi.1013076.ref039","doi-asserted-by":"crossref","DOI":"10.1016\/j.devcel.2022.08.008","article-title":"Spatiotemporal control of ERK pulse frequency coordinates fate decisions during mammary acinar morphogenesis","volume":"57","author":"P Ender","year":"2022","journal-title":"Dev Cell"},{"key":"pcbi.1013076.ref040","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1007\/978-1-4939-7154-1_3","article-title":"Single-Cell Imaging of ERK Signaling Using Fluorescent Biosensors","volume":"1636","author":"M Pargett","year":"2017","journal-title":"Methods Mol Biol"},{"issue":"8","key":"pcbi.1013076.ref041","doi-asserted-by":"crossref","DOI":"10.15252\/msb.20199110","article-title":"SBML level 3: an extensible format for the exchange and reuse of biological models","volume":"16","author":"S Keating","year":"2020","journal-title":"Mol Syst Biol"},{"issue":"1","key":"pcbi.1013076.ref042","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pcbi.1008646","article-title":"PEtab-Interoperable specification of parameter estimation problems in systems biology","volume":"17","author":"L Schmiester","year":"2021","journal-title":"PLoS Comput 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Methods"},{"key":"pcbi.1013076.ref046","author":"Pydstool","year":"2007"},{"issue":"7","key":"pcbi.1013076.ref047","doi-asserted-by":"crossref","first-page":"676","DOI":"10.1038\/nmeth.2019","article-title":"Fiji: an open-source platform for biological-image analysis","volume":"9","author":"J Schindelin","year":"2012","journal-title":"Nat Methods"},{"key":"pcbi.1013076.ref048","doi-asserted-by":"crossref","unstructured":"Schmidt U, Weigert M, Broaddus C, Myers G. Cell detection with star-convex polygons. In: Frangi AF, Schnabel JA, Davatzikos C, Alberola-L\u00f3pez C, Fichtinger G (Editors). Medical image computing and computer assisted intervention \u2013 MICCAI 2018. Cham: Springer International Publishing. 2018. 265\u201373.","DOI":"10.1007\/978-3-030-00934-2_30"},{"issue":"22","key":"pcbi.1013076.ref049","doi-asserted-by":"crossref","first-page":"3532","DOI":"10.1093\/bioinformatics\/btw413","article-title":"MorphoLibJ: integrated library and plugins for mathematical morphology with ImageJ","volume":"32","author":"D Legland","year":"2016","journal-title":"Bioinformatics"},{"issue":"7","key":"pcbi.1013076.ref050","doi-asserted-by":"crossref","first-page":"741","DOI":"10.1177\/25.7.70454","article-title":"Automatic measurement of sister chromatid exchange frequency","volume":"25","author":"GW Zack","year":"1977","journal-title":"J Histochem Cytochem"}],"updated-by":[{"DOI":"10.1371\/journal.pcbi.1013076","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2025,5,29]],"date-time":"2025-05-29T00:00:00Z","timestamp":1748476800000}}],"container-title":["PLOS Computational Biology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pcbi.1013076","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,5,29]],"date-time":"2025-05-29T14:00:08Z","timestamp":1748527208000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pcbi.1013076"}},"subtitle":[],"editor":[{"given":"Melissa L.","family":"Kemp","sequence":"first","affiliation":[]}],"short-title":[],"issued":{"date-parts":[[2025,5,12]]},"references-count":50,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2025,5,12]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pcbi.1013076","relation":{},"ISSN":["1553-7358"],"issn-type":[{"value":"1553-7358","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,5,12]]}}}