Letter | Published:

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

Nature Genetics volume 39, pages 13761383 (2007) | Download Citation

Abstract

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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Acknowledgements

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.

Author information

Author notes

    • Carme Cortina
    •  & Sergio Palomo-Ponce

    These authors contributed equally to this work.

Affiliations

  1. Oncology Programme, Institute for Research in Biomedicine (IRB), Josep Samitier 1-5, 08028 Barcelona. Spain.

    • Carme Cortina
    • , Sergio Palomo-Ponce
    • , Juan Luis Fernández-Masip
    • , Ana Vivancos
    • , Gavin Whissell
    • , Mireia Humà
    • , Nerea Peiró
    • , Lourdes Gallego
    • , Suzanne Jonkheer
    • , Elena Sancho
    •  & Eduard Batlle
  2. Department of Pathology, Hospital Universitari del Mar, Universitat Autònoma de Barcelona, Barcelona, Spain.

    • Mar Iglesias
    •  & Josep Lloreta
  3. Centre de Biologie du Developpement, CNRS/UPS, 118 Route de Narbonne, Bat 4R3, 31062 Toulouse cedex 4, France.

    • Alice Davy
  4. Institució Catalana de Recerca i Estudis Avançats (ICREA).

    • Eduard Batlle

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Contributions

C.C. generated and analyzed in vitro models of tumor cell compartmentalization. S.P.-P. generated and analyzed mice lacking ephrin-B1 in the intestine and tumor phenotypes and performed a wide range of stainings. M.I. performed the quantification and histopathological assessment of mice tumor phenotypes. J.L.F.-M. performed analysis of EphB3 activation, and A.V. worked on the analysis of E-cadherin in cell models. G.W. performed Wnt reporter and qRT-PCR assays. M.H., N.P., L.G. and S.J. provided technical assistance with histology and mice work. A.D. generated ephrin-B1 conditional mice. J.L. performed transmission electron microscopy analysis, E.S. provided project supervision and contributed to the writing, and E.B. provided the general concept, design of study, supervision and manuscript writing.

Corresponding author

Correspondence to Eduard Batlle.

Supplementary information

PDF files

  1. 1.

    Supplementary Text and Figures

    Supplementary Figures 1-10, Supplementary Table 1, Supplementary Discussion, Supplementary Methods

Videos

  1. 1.

    Supplementary Video 1

    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.

  2. 2.

    Supplementary Video 2

    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.

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DOI

https://doi.org/10.1038/ng.2007.11

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