1. Cancer Biology
  2. Stem Cells and Regenerative Medicine
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HNF1A is a novel oncogene that regulates human pancreatic cancer stem cell properties

Research Article
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Cite this article as: eLife 2018;7:e33947 doi: 10.7554/eLife.33947

Abstract

The biological properties of pancreatic cancer stem cells (PCSCs) remain incompletely defined and the central regulators are unknown. By bioinformatic analysis of a human PCSC-enriched gene signature, we identified the transcription factor HNF1A as a putative central regulator of PCSC function. Levels of HNF1A and its target genes were found to be elevated in PCSCs and tumorspheres, and depletion of HNF1A resulted in growth inhibition, apoptosis, impaired tumorsphere formation, decreased PCSC marker expression, and downregulation of POU5F1/OCT4 expression. Conversely, HNF1A overexpression increased PCSC marker expression and tumorsphere formation in pancreatic cancer cells and drove PDA cell growth. Importantly, depletion of HNF1A in xenografts impaired tumor growth and depleted PCSC marker-positive cells in vivo. Finally, we established an HNF1A-dependent gene signature in PDA cells that significantly correlated with reduced survivability in patients. These findings identify HNF1A as a central transcriptional regulator of PCSC properties and novel oncogene in pancreatic ductal adenocarcinoma.

Data availability

All data from this study is available without limitations (GSE108151).

The following data sets were generated
The following previously published data sets were used
    1. Cancer Genome Atlas
    (2017) Cancer Genome Atlas
    No restrictions; all data available without limitations.

Article and author information

Author details

  1. Ethan V Abel

    Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-2922-617X
  2. Masashi Goto

    Translational Oncology Program, University of Michigan, Ann Arbor, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Brian Magnuson

    Department of Biostatistics, School of Public Health, University of Michigan, Ann Arbor, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Saji Abraham

    Translational Oncology Program, University of Michigan, Ann Arbor, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Nikita Ramanathan

    Translational Oncology Program, University of Michigan, Ann Arbor, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Emily Hotaling

    Translational Oncology Program, University of Michigan, Ann Arbor, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Anthony A Alaniz

    Translational Oncology Program, University of Michigan, Ann Arbor, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Chandan Kumar-Sinha

    Department of Pathology, University of Michigan, Ann Arbor, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. Michele L Dziubinski

    Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, United States
    Competing interests
    The authors declare that no competing interests exist.
  10. Sumithra Urs

    Translational Oncology Program, University of Michigan, Ann Arbor, United States
    Competing interests
    The authors declare that no competing interests exist.
  11. Lidong Wang

    Department of Surgery, New York University, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  12. Jiaqi Shi

    Department of Pathology, University of Michigan, Ann Arbor, United States
    Competing interests
    The authors declare that no competing interests exist.
  13. Meghna Waghray

    Translational Oncology Program, University of Michigan, Ann Arbor, United States
    Competing interests
    The authors declare that no competing interests exist.
  14. Mats Ljungman

    Department of Radiation Oncology, University of Michigan, Ann Arbor, United States
    Competing interests
    The authors declare that no competing interests exist.
  15. Howard C Crawford

    Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, United States
    Competing interests
    The authors declare that no competing interests exist.
  16. Diane M Simeone

    Department of Surgery, New York University, New York, United States
    For correspondence
    diane.simeone@nyumc.org
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-5142-3087

Funding

Gershenson Pancreatic Cancer Fund

  • Diane M Simeone

SKY Foundation

  • Howard C Crawford
  • Diane M Simeone

American Cancer Society (127662-PF-15-033-01-DDC)

  • Ethan V Abel

Pancreatic Cancer Action Network (16-70-25-ABEL)

  • Ethan V Abel

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

Ethics

Animal experimentation: All animal protocols were approved by University Committee for the Use and Care of Animals (UCUCA) at The University of Michigan. The animal welfare assurance number for this study is A3114-01. Every effort was made throughout this study to minimize stress to and suffering of animal subjects.

Human subjects: Patient samples were collected under a protocol approved by the IRB at the The University of Michigan. All patients gave informed consent. The human assurance number for this study is FWA00004969.

Reviewing Editor

  1. Richard M White, Memorial Sloan Kettering Cancer Center, United States

Publication history

  1. Received: November 29, 2017
  2. Accepted: August 1, 2018
  3. Accepted Manuscript published: August 3, 2018 (version 1)
  4. Version of Record published: September 4, 2018 (version 2)

Copyright

© 2018, Abel 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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