The genes encoding tyrosine kinase receptors EphB2 and EphB3 are β-catenin and Tcf4 target genes in colorectal cancer (CRC) and in normal intestinal cells1,2. In the intestinal epithelium, EphB signaling controls the positioning of cell types along the crypt-villus axis1. In CRC, EphB activity suppresses tumor progression beyond the earliest stages3,4. 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.
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We thank P. Soriano for providing ephrin-B1 conditional knockout mice, H. Clevers for reagents and support, L. Bardia for technical help with microscopy, N. Malats for help with statistics and D. Dominguez and the rest of the laboratory members for discussions and support. We thank D. Baltimore (Caltech) for the gift of the FUW vector backbone. This study was supported by a grant awarded to E.B. by the Ministerio de Educación y Ciencia (SAF2005-4891). C.C. and J.L.F.-M. were recipients of predoctoral fellowships from the Department de Educació i Universitats of the Catalonian government and A.V. holds a Juan de la Cierva Fellowship.
Supplementary Figures 1-10, Supplementary Table 1, Supplementary Discussion, Supplementary Methods (PDF 5077 kb)
Co115 cells infected with a control Ubq-GFP lentivirus (A) or with lentivirus bearing EphB2 (B) or EphB3 (C) cDNAs downstream of the ubiquitin promoter were recorded during 15 minutes (timer from -15 to 0) before the addition of recombinant crosslinked ephrin-B1/Fc protein to the medium. Cells were then filmed for 60 minutes. Movies show DIC images taken every 30 seconds. (MOV 4501 kb)
Ubq-EphB3 Co115 cells expressing a non-targeting control shRNA (A) or a shRNA targeting E-cadherin (B) were recorded during 15 minutes (timer from -15 to 0) before the addition of recombinant crosslinked ephrin-B1/Fc protein to the medium. Cells were then filmed for 190 minutes. Movies show DIC images taken every 30 seconds. (MOV 3249 kb)
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Cortina, C., Palomo-Ponce, S., Iglesias, M. et al. EphB–ephrin-B interactions suppress colorectal cancer progression by compartmentalizing tumor cells. Nat Genet 39, 1376–1383 (2007). https://doi.org/10.1038/ng.2007.11
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