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Here, we show that pre\u2010existing heterogeneity contributes to divergent outcomes following transforming growth factor\u2010beta 3 (TGF\u03b23) treatment. Flow cytometry, gene expression profiling and imaging revealed persistent variability in E\u2010cadherin (E\u2010cad) and epithelial cell adhesion molecule (EpCAM) expression, with differentially sorted subpopulations displaying distinct transcriptional responses. Remarkably, some single\u2010cell\u2010derived clones exhibited paradoxical\n                    <jats:italic>CDH1<\/jats:italic>\n                    upregulation during EMT, coinciding with\n                    <jats:italic>GRHL3<\/jats:italic>\n                    induction and reflecting context\u2010specific regulatory plasticity. Additionally, forskolin\u2010mediated cyclic adenosine monophosphate (cAMP) activation enhanced epithelial stability and modulated EMT dynamics by preserving membrane\u2010localised E\u2010cadherin without preventing transcriptional repression of\n                    <jats:italic>CDH1<\/jats:italic>\n                    . Comparison with an epithelial subclone model further demonstrated how baseline identity shapes EMT trajectories. Moreover,\n                    <jats:italic>in vivo<\/jats:italic>\n                    analysis using zebrafish xenografts revealed that intrinsic epithelial features were associated with differential dissemination potential, reinforcing the connection between cellular identity and metastatic behaviour. These findings underline the importance of accounting for inherent heterogeneity in EMT models and demonstrate how intrinsic regulatory states and extrinsic signals intersect to shape epithelial plasticity.\n                  <\/jats:p>","DOI":"10.1111\/febs.70458","type":"journal-article","created":{"date-parts":[[2026,2,17]],"date-time":"2026-02-17T11:26:23Z","timestamp":1771327583000},"page":"4814-4840","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Intrinsic cellular heterogeneity directs divergent epithelial\u2010to\u2010mesenchymal transition outcomes"],"prefix":"10.1111","volume":"293","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0282-783X","authenticated-orcid":false,"given":"Esin","family":"Ozkuru Sekeroglu","sequence":"first","affiliation":[{"name":"Izmir International Biomedicine and Genome Institute, Dokuz Eyl\u00fcl University  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