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

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

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

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

    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

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

    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

    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

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

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

Reviewing Editor

  1. Ewa Paluch, University College London, United Kingdom

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.

Version 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.

Metrics

  • 4,300
    Page views
  • 668
    Downloads
  • 47
    Citations

Article citation count generated by polling the highest count across the following sources: Crossref, Scopus, PubMed Central.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  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
(2015)
Defective apical extrusion signaling contributes to aggressive tumor hallmarks
eLife 4:e04069.
https://doi.org/10.7554/eLife.04069

Share this article

https://doi.org/10.7554/eLife.04069

Further reading

    1. Cell Biology
    Kazuki Hanaoka, Kensuke Nishikawa ... Kouichi Funato
    Research Article

    Membrane contact sites (MCSs) are junctures that perform important roles including coordinating lipid metabolism. Previous studies have indicated that vacuolar fission/fusion processes are coupled with modifications in the membrane lipid composition. However, it has been still unclear whether MCS-mediated lipid metabolism controls the vacuolar morphology. Here, we report that deletion of tricalbins (Tcb1, Tcb2, and Tcb3), tethering proteins at endoplasmic reticulum (ER)–plasma membrane (PM) and ER–Golgi contact sites, alters fusion/fission dynamics and causes vacuolar fragmentation in the yeast Saccharomyces cerevisiae. In addition, we show that the sphingolipid precursor phytosphingosine (PHS) accumulates in tricalbin-deleted cells, triggering the vacuolar division. Detachment of the nucleus–vacuole junction (NVJ), an important contact site between the vacuole and the perinuclear ER, restored vacuolar morphology in both cells subjected to high exogenous PHS and Tcb3-deleted cells, supporting that PHS transport across the NVJ induces vacuole division. Thus, our results suggest that vacuolar morphology is maintained by MCSs through the metabolism of sphingolipids.

    1. Cell Biology
    2. Chromosomes and Gene Expression
    Monica Salinas-Pena, Elena Rebollo, Albert Jordan
    Research Article

    Histone H1 participates in chromatin condensation and regulates nuclear processes. Human somatic cells may contain up to seven histone H1 variants, although their functional heterogeneity is not fully understood. Here, we have profiled the differential nuclear distribution of the somatic H1 repertoire in human cells through imaging techniques including super-resolution microscopy. H1 variants exhibit characteristic distribution patterns in both interphase and mitosis. H1.2, H1.3, and H1.5 are universally enriched at the nuclear periphery in all cell lines analyzed and co-localize with compacted DNA. H1.0 shows a less pronounced peripheral localization, with apparent variability among different cell lines. On the other hand, H1.4 and H1X are distributed throughout the nucleus, being H1X universally enriched in high-GC regions and abundant in the nucleoli. Interestingly, H1.4 and H1.0 show a more peripheral distribution in cell lines lacking H1.3 and H1.5. The differential distribution patterns of H1 suggest specific functionalities in organizing lamina-associated domains or nucleolar activity, which is further supported by a distinct response of H1X or phosphorylated H1.4 to the inhibition of ribosomal DNA transcription. Moreover, H1 variants depletion affects chromatin structure in a variant-specific manner. Concretely, H1.2 knock-down, either alone or combined, triggers a global chromatin decompaction. Overall, imaging has allowed us to distinguish H1 variants distribution beyond the segregation in two groups denoted by previous ChIP-Seq determinations. Our results support H1 variants heterogeneity and suggest that variant-specific functionality can be shared between different cell types.