The acinar differentiation determinant PTF1A inhibits initiation of pancreatic ductal adenocarcinoma

  1. Nathan M Krah
  2. Jean-Paul De La O
  3. Galvin H Swift
  4. Chinh Q Hoang
  5. Spencer G Willet
  6. Fong Chen Pan
  7. Gabriela M Cash
  8. Mary P Bronner
  9. Christopher V E Wright
  10. Raymond J MacDonald
  11. L Charles Murtaugh  Is a corresponding author
  1. University of Utah, United States
  2. University of Texas Southwestern Medical Center, United States
  3. Vanderbilt University Medical Center, United States

Abstract

Understanding the initiation and progression of pancreatic ductal adenocarcinoma (PDAC) may provide therapeutic strategies for this deadly disease. Recently, we and others made the surprising finding that PDAC and its preinvasive precursors, pancreatic intraepithelial neoplasia (PanIN), arise via reprogramming of mature acinar cells. We therefore hypothesized that the master regulator of acinar differentiation, PTF1A, could play a central role in suppressing PDAC initiation. Here, we demonstrate that PTF1A expression is lost in both mouse and human PanINs, and that this downregulation is functionally imperative in mice for acinar reprogramming by oncogenic KRAS. Loss of Ptf1a alone is sufficient to induce acinar-to-ductal metaplasia, potentiate inflammation, and induce a KRAS-permissive, PDAC-like gene expression profile. As a result, Ptf1a-deficient acinar cells are dramatically sensitized to KRAS transformation, and reduced Ptf1a greatly accelerates development of invasive PDAC. Together, these data indicate that cell differentiation regulators constitute a new tumor suppressive mechanism in the pancreas.

Article and author information

Author details

  1. Nathan M Krah

    Department of Human Genetics, University of Utah, Salt Lake City, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Jean-Paul De La O

    Department of Human Genetics, University of Utah, Salt Lake City, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Galvin H Swift

    Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Chinh Q Hoang

    Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Spencer G Willet

    Department of Cell and Developmental Biology, Vanderbilt University Medical Center, Nashville, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Fong Chen Pan

    Department of Cell and Developmental Biology, Vanderbilt University Medical Center, Nashville, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Gabriela M Cash

    Department of Human Genetics, University of Utah, Salt Lake City, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Mary P Bronner

    Department of Pathology, Huntsman Cancer Hospital, University of Utah, Salt Lake City, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. Christopher V E Wright

    Department of Cell and Developmental Biology, Vanderbilt University Medical Center, Nashville, United States
    Competing interests
    The authors declare that no competing interests exist.
  10. Raymond J MacDonald

    Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, United States
    Competing interests
    The authors declare that no competing interests exist.
  11. L Charles Murtaugh

    Department of Human Genetics, University of Utah, Salt Lake City, United States
    For correspondence
    murtaugh@genetics.utah.edu
    Competing interests
    The authors declare that no competing interests exist.

Ethics

Animal experimentation: This study was performed according to institutional and National Institutes of Health guidelines for animal research (Guide for the Care and Use of Laboratory Animals), and followed protocols approved by the institutional animal care and use committees of the University of Utah (protocol #13-09009), University of Texas Southwestern Medical Center (protocol #2013-0008) and Vanderbilt University (protocol #M10/106).

Reviewing Editor

  1. Michael R Green, Howard Hughes Medical Institute, University of Massachusetts Medical School, United States

Publication history

  1. Received: February 21, 2015
  2. Accepted: July 7, 2015
  3. Accepted Manuscript published: July 7, 2015 (version 1)
  4. Version of Record published: August 14, 2015 (version 2)

Copyright

© 2015, Krah 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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  1. Nathan M Krah
  2. Jean-Paul De La O
  3. Galvin H Swift
  4. Chinh Q Hoang
  5. Spencer G Willet
  6. Fong Chen Pan
  7. Gabriela M Cash
  8. Mary P Bronner
  9. Christopher V E Wright
  10. Raymond J MacDonald
  11. L Charles Murtaugh
(2015)
The acinar differentiation determinant PTF1A inhibits initiation of pancreatic ductal adenocarcinoma
eLife 4:e07125.
https://doi.org/10.7554/eLife.07125
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