The ECM and tissue architecture are major determinants of early invasion mediated by E-cadherin dysfunction Articles uri icon

authors

  • MELO, SORAIA
  • GUERRERO CONTRERAS, MARIA PILAR
  • MOREIRA SOARES, MAURICIO
  • BORDIN, JOSE RAFAEL
  • CARNEIRO, FATIMA
  • CARNEIRO, PATRICIA
  • DIAS, MARIA BEATRIZ
  • CARVALHO, JOAO
  • FIGUEIREDO, JOANA
  • SERUCA, RAQUEL
  • TRAVASSO, RUI D.M.

publication date

  • November 2023

volume

  • 6

International Standard Serial Number (ISSN)

  • 2399-3642

abstract

  • 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.

subjects

  • Mathematics