EphB–ephrin-B interactions suppress colorectal cancer progression by compartmentalizing tumor cells

The genes encoding tyrosine kinase receptors EphB2 and EphB3 are β-catenin and Tcf4 target genes in colorectal cancer (CRC) and in normal intestinal cells 1 , 2 . In the intestinal epithelium, EphB signaling controls the positioning of cell types along the crypt-villus axis 1 . In CRC, EphB activity suppresses tumor progression beyond the earliest stages 3 , 4 . Here we show that EphB receptors compartmentalize the expansion of CRC cells through a mechanism dependent on E-cadherin–mediated adhesion. We demonstrate that EphB-mediated compartmentalization restricts the spreading of EphB-expressing tumor cells into ephrin-B1–positive territories in vitro and in vivo . Our results indicate that CRC cells must silence EphB expression to avoid repulsive interactions imposed by normal ephrin-B1–expressing intestinal cells at the onset of tumorigenesis.