Loss of E-Cadherin Promotes Metastasis via Multiple Downstream Transcriptional Pathways

TLDR

Loss of the epithelial adhesion molecule E‑cadherin is thought to enable metastasis by disrupting intercellular contacts—an early step in metastatic dissemination. The study aims to dissect the molecular basis of E‑cadherin loss–induced metastasis by employing two distinct inhibition strategies that separate adhesion from signaling roles. The authors inhibit E‑cadherin function using two approaches that differentiate between its adhesion and intracellular signaling functions. Disrupting cell‑cell contacts alone does not promote metastasis, whereas complete loss of E‑cadherin drives EMT, invasiveness, anoikis resistance, and metastasis through β‑catenin–dependent and Twist‑mediated transcriptional programs. Cancer Res 2008;68(10):3645–53.

Abstract

Abstract Loss of the epithelial adhesion molecule E-cadherin is thought to enable metastasis by disrupting intercellular contacts—an early step in metastatic dissemination. To further investigate the molecular basis of this notion, we use two methods to inhibit E-cadherin function that distinguish between E-cadherin's cell-cell adhesion and intracellular signaling functions. Whereas the disruption of cell-cell contacts alone does not enable metastasis, the loss of E-cadherin protein does, through induction of an epithelial-to-mesenchymal transition, invasiveness, and anoikis resistance. We find the E-cadherin binding partner β-catenin to be necessary, but not sufficient, for induction of these phenotypes. In addition, gene expression analysis shows that E-cadherin loss results in the induction of multiple transcription factors, at least one of which, Twist, is necessary for E-cadherin loss–induced metastasis. These findings indicate that E-cadherin loss in tumors contributes to metastatic dissemination by inducing wide-ranging transcriptional and functional changes. [Cancer Res 2008;68(10):3645–53]