E-钙粘蛋白的种系突变导致遗传性弥漫性胃癌（HDGC），这是一种高度侵袭性的癌症综合征，其特征是发生弥漫型胃癌和小叶乳腺癌。在这种疾病中，E-钙粘蛋白缺陷细胞从很早的阶段就被发现侵入邻近的基质。尽管E-钙粘蛋白损失已被确定为触发事件，但侵入过程的其他决定因素仍然很大程度上未知。在此，我们开发了一种实验策略，包括使用与 HDGC 相关的 E-钙粘蛋白突变体进行体外挤压测定，以及概括上皮动力学及其与细胞外基质 (ECM) 相互作用的数学模型。在体外，我们验证了 E-钙粘蛋白功能障碍细胞从上皮单层分离并从基底挤出到 ECM 中。通过相场建模，我们证明，除了细胞间粘附力的丧失之外，ECM 附着的增加还进一步提高了基础挤出效率。重要的是，通过结合相场和顶点模型模拟，我们表明胃腺的圆柱形结构强烈促进细胞的侵袭能力。此外，我们使用上皮挤压的耗散粒子动力学模拟验证了我们的发现。总体而言，我们提供了第一个证据，证明癌细胞侵袭是细胞间连接缺陷、与 ECM 相互作用异常以及有利的 3D 组织结构的结果。© 2023。作者。

Germline mutations of E-cadherin cause Hereditary Diffuse Gastric Cancer (HDGC), a highly invasive cancer syndrome characterised by the occurrence of diffuse-type gastric carcinoma and lobular breast cancer. 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's 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.© 2023. The Author(s).