Integrin β1 orchestrates the abnormal cell-matrix attachment and invasive behaviour of E-cadherin dysfunctional cells

Background Tumour 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). Methods To 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). Results Here, 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 beta 1 activation. Integrin beta 1 synergizes with E-cadherin dysfunction, promoting cell scattering and invasion. The significance of the E-cadherin-Integrin beta 1 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 beta 1 levels. Conclusions Integrin beta 1 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.

Automated summary

Research has shown that mutations in E-cadherin lead to abnormal interactions of cells with specific ECM components, resulting in increased traction forces and activation of Integrin beta 1, which promotes cell scattering and invasion. This crosstalk between E-cadherin and Integrin beta 1 is validated in Drosophila models and human gastric carcinomas, where low E-cadherin and high Integrin beta 1 levels are associated with increased tumour grade and poor survival. Integrin beta 1 is identified as a key mediator of invasion in carcinomas with E-cadherin impairment and a biomarker of poor prognosis in gastric cancer.