title: EphA2 Drives the Segregation of Ras-Transformed Epithelial Cells from Normal Neighbors.
abstract: In epithelial tissues, cells expressing oncogenic Ras (hereafter RasV12 cells) are detected by normal neighbors and as a result are often extruded from the tissue [1-6]. RasV12 cells are eliminated apically, suggesting that extrusion may be a tumor-suppressive process. Extrusion depends on E-cadherin-based cell-cell adhesions and signaling to the actin-myosin cytoskeleton [2, 6]. However, the signals underlying detection of the RasV12 cell and triggering extrusion are poorly understood. Here we identify differential EphA2 signaling as the mechanism by which RasV12 cells are detected in epithelial cell sheets. Cell-cell interactions between normal cells and RasV12 cells trigger ephrin-A-EphA2 signaling, which induces a cell repulsion response in RasV12 cells. Concomitantly, RasV12 cell contractility increases in an EphA2-dependent manner. Together, these responses drive the separation of RasV12 cells from normal cells. In the absence of ephrin-A-EphA2 signals, RasV12 cells integrate with normal cells and adopt a pro-invasive morphology. We also show that Drosophila Eph (DEph) is detected in segregating clones of RasV12 cells and is functionally required to drive segregation of RasV12 cells in vivo, suggesting that our in vitro findings are conserved in evolution. We propose that expression of RasV12 in single or small clusters of cells within a healthy epithelium creates ectopic EphA2 boundaries, which drive the segregation and elimination of the transformed cell from the tissue. Thus, deregulation of Eph/ephrin would allow RasV12 cells to go undetected and expand within an epithelium.
authors.affiliation: European Cancer Stem Cell Research Institute, Cardiff University, Hadyn Ellis Building, Maindy Road, Cardiff CF24 4HQ, UK.
authors.forename: Sean
authors.initials: S
authors.lastname: Porazinski
authors.affiliation: European Cancer Stem Cell Research Institute, Cardiff University, Hadyn Ellis Building, Maindy Road, Cardiff CF24 4HQ, UK.
authors.forename: Joaquín
authors.initials: J
authors.lastname: de Navascués
authors.affiliation: Division of Molecular Oncology, Institute for Genetic Medicine, Hokkaido University Graduate School of Chemical Sciences and Engineering, Kita 15, Nishi 7, Kita-ku, Sapporo, Hokkaido 060-0815, Japan.
authors.forename: Yuta
authors.initials: Y
authors.lastname: Yako
authors.affiliation: European Cancer Stem Cell Research Institute, Cardiff University, Hadyn Ellis Building, Maindy Road, Cardiff CF24 4HQ, UK.
authors.forename: William
authors.initials: W
authors.lastname: Hill
authors.affiliation: European Cancer Stem Cell Research Institute, Cardiff University, Hadyn Ellis Building, Maindy Road, Cardiff CF24 4HQ, UK.
authors.forename: Matthew Robert
authors.initials: MR
authors.lastname: Jones
authors.affiliation: European Cancer Stem Cell Research Institute, Cardiff University, Hadyn Ellis Building, Maindy Road, Cardiff CF24 4HQ, UK.
authors.forename: Robert
authors.initials: R
authors.lastname: Maddison
authors.affiliation: Division of Molecular Oncology, Institute for Genetic Medicine, Hokkaido University Graduate School of Chemical Sciences and Engineering, Kita 15, Nishi 7, Kita-ku, Sapporo, Hokkaido 060-0815, Japan.
authors.forename: Yasuyuki
authors.initials: Y
authors.lastname: Fujita
authors.affiliation: European Cancer Stem Cell Research Institute, Cardiff University, Hadyn Ellis Building, Maindy Road, Cardiff CF24 4HQ, UK. Electronic address: hoganc@cardiff.ac.uk.
authors.forename: Catherine
authors.initials: C
authors.lastname: Hogan
mesh_terms: D000818:Animals; D002450:Cell Communication / Q000502:physiology; D002478:Cells, Cultured; D004847:Epithelial Cells / Q000502:physiology*; D005786:Gene Expression Regulation; D036104:Receptor, EphA2 / Q000235:genetics / Q000378:metabolism*; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D036104:Receptor, EphA2; D018631:ras Proteins
keywords: EphA2; Ras-transformed; Src; actin-myosin cytoskeleton; cell segregation; cell-cell interaction; contractility; extrusion; repulsion