1. Cell Biology
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Defective apical extrusion signaling contributes to aggressive tumor hallmarks

  1. Yapeng Gu
  2. Jill Shea
  3. Gloria Slattum
  4. Matthew A Firpo
  5. Margaret Alexander
  6. Sean J Mulvihill
  7. Vita M Golubovskaya
  8. Jody Rosenblatt Is a corresponding author
  1. University of Utah, United States
  2. Roswell Park Cancer Institute, United States
Research Article
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Cite as: eLife 2015;4:e04069 doi: 10.7554/eLife.04069

Abstract

When epithelia become too crowded, some cells are extruded that later die. To extrude, a cell produces the lipid, Sphingosine 1-Phosphate (S1P), which activates S1P2 receptors in neighboring cells that seamlessly squeeze the cell out of the epithelium. Here, we find that extrusion defects can contribute to carcinogenesis and tumor progression. Tumors or epithelia lacking S1P2 cannot extrude cells apically and instead form apoptotic-resistant masses, possess poor barrier function, and shift extrusion basally beneath the epithelium, providing a potential mechanism for cell invasion. Exogenous S1P2 expression is sufficient to rescue apical extrusion, cell death, and reduce orthotopic pancreatic tumors and their metastases. Focal Adhesion Kinase (FAK) inhibitor can bypass extrusion defects and could, therefore, target pancreatic, lung, and colon tumors that lack S1P2 without affecting wild-type tissue.

Article and author information

Author details

  1. Yapeng Gu

    1. Huntsman Cancer Institute, University of Utah, Salt Lake City, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Jill Shea

    1. Department of Surgery, University of Utah, Salt Lake City, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Gloria Slattum

    1. Huntsman Cancer Institute, University of Utah, Salt Lake City, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Matthew A Firpo

    1. Department of Surgery, University of Utah, Salt Lake City, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Margaret Alexander

    1. Huntsman Cancer Institute, University of Utah, Salt Lake City, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Sean J Mulvihill

    1. Department of Surgery, University of Utah, Salt Lake City, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Vita M Golubovskaya

    1. Department of Surgical Oncology, Roswell Park Cancer Institute, Buffalo, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Jody Rosenblatt

    1. Huntsman Cancer Institute, University of Utah, Salt Lake City, United States
    For correspondence
    1. jody.rosenblatt@hci.utah.edu
    Competing interests
    The authors declare that no competing interests exist.

Ethics

Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All of the animals were handled according to approved institutional animal care and use committee (IACUC) protocols (#13-06006) of the University of Utah. The protocol was approved by the University of Utah IACUC board.

Human subjects: The use of human tissue in this study was approved by the University of Utah Institutional Review Board. Tissue sections were obtained from excess clinical pathology tissue from patients resected for pancreatic adenocarcinoma at the University of Utah Huntsman Cancer Institute with appropriate informed consent for use of samples for research purposes (IRB_00010924). Human tissue sample were deidentified and informed consent was obtained from all study participants. The protocol was approved and monitored by the University of Utah Institutional Review Board.

Reviewing Editor

  1. Ewa Paluch, Reviewing Editor, University College London, United Kingdom

Publication history

  1. Received: July 17, 2014
  2. Accepted: January 22, 2015
  3. Accepted Manuscript published: January 26, 2015 (version 1)
  4. Version of Record published: February 10, 2015 (version 2)

Copyright

© 2015, Gu et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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