Abstract

BackgroundTumour progression relies on the ability of cancer cells to penetrate and invade neighbouring tissues. E-cadherin loss is associated with increased cell invasion in gastric carcinoma, and germline mutations of the E-cadherin gene are causative of hereditary diffuse gastric cancer. Although E-cadherin dysfunction impacts cell–cell adhesion, cell dissemination also requires an imbalance of adhesion to the extracellular matrix (ECM).MethodsTo identify ECM components and receptors relevant for adhesion of E-cadherin dysfunctional cells, we implemented a novel ECM microarray platform coupled with molecular interaction networks. The functional role of putative candidates was determined by combining micropattern traction microscopy, protein modulation and in vivo approaches, as well as transcriptomic data of 262 gastric carcinoma samples, retrieved from the cancer genome atlas (TCGA).ResultsHere, we show that E-cadherin mutations induce an abnormal interplay of cells with specific components of the ECM, which encompasses increased traction forces and Integrin β1 activation. Integrin β1 synergizes with E-cadherin dysfunction, promoting cell scattering and invasion. The significance of the E-cadherin-Integrin β1 crosstalk was validated in Drosophila models and found to be consistent with evidence from human gastric carcinomas, where increased tumour grade and poor survival are associated with low E-cadherin and high Integrin β1 levels.ConclusionsIntegrin β1 is a key mediator of invasion in carcinomas with E-cadherin impairment and should be regarded as a biomarker of poor prognosis in gastric cancer.

Highlights

  • E-cadherin is an essential molecule for epithelial homeostasis by regulating epithelial architecture and tissue integrity [1]

  • Our results demonstrate that E-cadherin loss modifies physical and biochemical features of the cell-matrix interaction, and pinpoint Integrin β1 as the key player in cadherin-mediated invasion

  • To investigate the effects of variants associated with hereditary diffuse gastric cancer syndrome (HDGC) in cell-matrix interactions, we have used cells transfected with wild-type E-cadherin or the different variants in an array of 36 combinations of extracellular matrix (ECM) proteins (Fig. 1A)

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Summary

Introduction

E-cadherin is an essential molecule for epithelial homeostasis by regulating epithelial architecture and tissue integrity [1]. Precursor lesions of invasive gastric cancer have been identified in CDH1 mutation carriers as in situ signet ring cell carcinoma (SRCC) or pagetoid spread of signet ring cells below the preserved epithelium of glands [6, 7]. These early gastric lesions are a hallmark of the disease and provide unique evidence that, in the initial steps of the neoplastic process, E-cadherin dysfunctional cells lack cellular cohesion but maintain a close contact with the basement membrane—a specialized extracellular matrix (ECM) that supports and fine-tunes cellular functions [6, 7]. Conclusions Integrin β1 is a key mediator of invasion in carcinomas with E-cadherin impairment and should be regarded as a biomarker of poor prognosis in gastric cancer

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