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Epithelial-Myeloid cell crosstalk regulates acinar cell plasticity and pancreatic remodeling in mice

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Cite this article as: eLife 2017;6:e27388 doi: 10.7554/eLife.27388

Abstract

Dedifferentiation of acini to duct-like cells occurs during the physiologic damage response in the pancreas, but this process can be co-opted by oncogenic Kras to drive carcinogenesis. Myeloid cells infiltrate the pancreas during the onset of pancreatic cancer, and promote carcinogenesis. Here, we show that the function of infiltrating myeloid cells is regulated by oncogenic Kras expressed in epithelial cells. In the presence of oncogenic Kras, myeloid cells promote acinar dedifferentiation and carcinogenesis. Upon inactivation of oncogenic Kras, myeloid cells promote re-differentiation of acinar cells, remodeling of the fibrotic stroma and tissue repair. Intriguingly, both aspects of myeloid cell activity depend, at least in part, on activation of EGFR/MAPK signaling, with different subsets of ligands and receptors in different target cells promoting carcinogenesis or repair, respectively. Thus, the cross-talk between epithelial cells and infiltrating myeloid cells determines the balance between tissue repair and carcinogenesis in the pancreas.

Article and author information

Author details

  1. Yaqing Zhang

    Department of Surgery, University of Michigan, Ann Arbor, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Wei Yan

    Department of Surgery, University of Michigan, Ann Arbor, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Esha Mathew

    Program in Cellular and Molecular Biology, University of Michigan, Ann Arbor, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Kevin T Kane

    Department of Surgery, University of Michigan, Ann Arbor, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Arthur Brannon

    Program in Cellular and Molecular Biology, University of Michigan, Ann Arbor, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Maeva Adoumie

    College of Literature, Science, and the Arts, University of Michigan, Ann Arbor, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Alekya Vinta

    College of Literature, Science, and the Arts, University of Michigan, Ann Arbor, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Howard C Crawford

    Molecular and Integrative Physiology, University of Michigan, Ann Arbor, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. Marina Pasca di Magliano

    Department of Surgery, University of Michigan, Ann Arbor, United States
    For correspondence
    marinapa@umich.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-9632-9035

Funding

University of Michigan (Biological Scholar Program)

  • Marina Pasca di Magliano

American Cancer Society (Kras and the Inflammatory Microenvironment in Pancreatic Cancer)

  • Marina Pasca di Magliano

Elsa U. Pardee Foundation (Targeting Tumor Infiltrating Immune Cells as a Therapeutic Strategy in Pancreatic Cancer)

  • Marina Pasca di Magliano

National Cancer Institute (NCI-1R01CA151588)

  • Marina Pasca di Magliano

National Cancer Institute (3-P30-CA-046592-28-S2)

  • Marina Pasca di Magliano

National Cancer Institute (3-P30-CA-046592-28-S2)

  • Howard C Crawford

National Institutes of Health (University of Michigan Program in Cellular and Molecular Biology training grant NIH T32 GM007315)

  • Esha Mathew

National Institutes of Health (University of Michigan Gastrointestinal Training Grant NIH T32 DK094775)

  • Esha Mathew

National Cancer Institute (P30-CA-046592)

  • Marina Pasca di Magliano

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

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 (PRO00005959) of the University of Michigan. The protocol was approved by the University Committee on Use and Care of Animals (UCUCA) of the University of Michigan on 11/17/2014. The current protocol is valid until 11/17/2017. For the pancreatitis experiments and tumorigenesis experiments, strict guidelines were followed to minimize suffering of the animals. Animal activity levels and weight were monitored throughout the experiments.

Reviewing Editor

  1. Satyajit Rath, Agharkar Research Institute (ARI) and Indian Institute of Science Education and Research (IISER), India

Publication history

  1. Received: April 1, 2017
  2. Accepted: October 4, 2017
  3. Accepted Manuscript published: October 5, 2017 (version 1)
  4. Version of Record published: November 16, 2017 (version 2)

Copyright

© 2017, Zhang 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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Further reading

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