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In this disease, E-cadherin-defective cells are detected invading the adjacent stroma since very early stages. Although E-cadherin loss is well established as a triggering event, other determinants of the invasive process persist largely unknown. Herein, we develop an experimental strategy that comprises in vitro extrusion assays using E-cadherin mutants associated to HDGC, as well as mathematical models epitomising epithelial dynamics and its interaction with the extracellular matrix (ECM). In vitro, we verify that E-cadherin dysfunctional cells detach from the epithelial monolayer and extrude basally into the ECM. Through phase-field modelling we demonstrate that, aside from loss of cell-cell adhesion, increased ECM attachment further raises basal extrusion efficiency. Importantly, by combining phase-field and vertex model simulations, we show that the cylindrical structure of gastric glands strongly promotes the cell\u2019s invasive ability. Moreover, we validate our findings using a dissipative particle dynamics simulation of epithelial extrusion. Overall, we provide the first evidence that cancer cell invasion is the outcome of defective cell-cell linkages, abnormal interplay with the ECM, and a favourable 3D tissue structure.<\/jats:p>","DOI":"10.1038\/s42003-023-05482-x","type":"journal-article","created":{"date-parts":[[2023,11,8]],"date-time":"2023-11-08T12:02:09Z","timestamp":1699444929000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["The ECM and tissue architecture are major determinants of early invasion mediated by E-cadherin dysfunction"],"prefix":"10.1038","volume":"6","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0278-0827","authenticated-orcid":false,"given":"Soraia","family":"Melo","sequence":"first","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5522-7339","authenticated-orcid":false,"given":"Pilar","family":"Guerrero","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9928-7256","authenticated-orcid":false,"given":"Maur\u00edcio","family":"Moreira Soares","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8025-6529","authenticated-orcid":false,"given":"Jos\u00e9 Rafael","family":"Bordin","sequence":"additional","affiliation":[]},{"given":"F\u00e1tima","family":"Carneiro","sequence":"additional","affiliation":[]},{"given":"Patr\u00edcia","family":"Carneiro","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7429-0619","authenticated-orcid":false,"given":"Maria Beatriz","family":"Dias","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3015-7821","authenticated-orcid":false,"given":"Jo\u00e3o","family":"Carvalho","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1590-1974","authenticated-orcid":false,"given":"Joana","family":"Figueiredo","sequence":"additional","affiliation":[]},{"given":"Raquel","family":"Seruca","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6078-0721","authenticated-orcid":false,"given":"Rui D. 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