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Lactate-mediated epigenetic reprogramming regulates formation of human pancreatic cancer-associated fibroblasts

  1. Tushar D Bhagat
  2. Dagny Von Ahrens
  3. Meelad Dawlaty
  4. Yiyu Zou
  5. Joelle Baddour
  6. Abhinav Achreja
  7. Hongyun Zhao
  8. Lifeng Yang
  9. Brijesh Patel
  10. Changsoo Kwak
  11. Gaurav S Choudhary
  12. Shanisha Gordon-Mitchell
  13. Srinivas Aluri
  14. Sanchari Bhattacharyya
  15. Srabani Sahu
  16. Yiting Yu
  17. Matthias Bartenstein
  18. Orsi Giricz
  19. Masako Suzuki
  20. Davendra Sohal
  21. Sonal Gupta
  22. Paola A Guerrero
  23. Surinder Batra
  24. Michael Goggins
  25. Ulrich Steidl
  26. John Greally
  27. Beamon Agarwal
  28. Kith Pradhan
  29. Debabrata Banerjee
  30. Deepak Nagrath  Is a corresponding author
  31. Anirban Maitra  Is a corresponding author
  32. Amit Verma  Is a corresponding author
  1. Albert Einstein College of Medicine, United States
  2. University of Michigan, United States
  3. Rutgers University, United States
  4. University of Texas MD Anderson Cancer Center, United States
  5. Cleveland Clinic, United States
  6. University of Nebraska Medical Center, United States
  7. Johns Hopkins University, United States
  8. GenomeRxUs LLC, United States
Research Article
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Cite this article as: eLife 2019;8:e50663 doi: 10.7554/eLife.50663

Abstract

Even though pancreatic ductal adenocarcinoma (PDAC) is associated with fibrotic stroma, the molecular pathways regulating the formation of cancer associated fibroblasts (CAFs) are not well elucidated. An epigenomic analysis of patient-derived and de-novo generated CAFs demonstrated widespread loss of cytosine methylation that was associated with overexpression of various inflammatory transcripts including CXCR4. Co-culture of neoplastic cells with CAFs led to increased invasiveness that was abrogated by inhibition of CXCR4. Metabolite tracing revealed that lactate produced by neoplastic cells leads to increased production of alpha-ketoglutarate (aKG) within mesenchymal stem cells (MSCs). In turn, aKG mediated activation of the demethylase TET enzyme led to decreased cytosine methylation and increased hydroxymethylation during de novo differentiation of MSCs to CAF. Co-injection of neoplastic cells with TET-deficient MSCs inhibited tumor growth in vivo. Thus, in PDAC, a tumor-mediated lactate flux is associated with widespread epigenomic reprogramming that is seen during CAF formation.

Article and author information

Author details

  1. Tushar D Bhagat

    Albert Einstein College of Medicine, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-4527-5505
  2. Dagny Von Ahrens

    Albert Einstein College of Medicine, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Meelad Dawlaty

    Albert Einstein College of Medicine, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Yiyu Zou

    Albert Einstein College of Medicine, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Joelle Baddour

    Department of Biomedical Engineering, University of Michigan, Ann Arbor, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Abhinav Achreja

    Department of Biomedical Engineering, University of Michigan, Ann Arbor, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Hongyun Zhao

    Department of Biomedical Engineering, University of Michigan, Ann Arbor, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Lifeng Yang

    Department of Biomedical Engineering, University of Michigan, Ann Arbor, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. Brijesh Patel

    Rutgers University, New Brunswick, United States
    Competing interests
    The authors declare that no competing interests exist.
  10. Changsoo Kwak

    Department of Pathology, University of Texas MD Anderson Cancer Center, Houston, United States
    Competing interests
    The authors declare that no competing interests exist.
  11. Gaurav S Choudhary

    Albert Einstein College of Medicine, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  12. Shanisha Gordon-Mitchell

    Albert Einstein College of Medicine, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  13. Srinivas Aluri

    Albert Einstein College of Medicine, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  14. Sanchari Bhattacharyya

    Albert Einstein College of Medicine, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  15. Srabani Sahu

    Albert Einstein College of Medicine, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  16. Yiting Yu

    Albert Einstein College of Medicine, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  17. Matthias Bartenstein

    Albert Einstein College of Medicine, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-0908-770X
  18. Orsi Giricz

    Albert Einstein College of Medicine, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  19. Masako Suzuki

    Albert Einstein College of Medicine, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  20. Davendra Sohal

    Department of Medicine, Cleveland Clinic, Cleveland, United States
    Competing interests
    The authors declare that no competing interests exist.
  21. Sonal Gupta

    Department of Pathology, University of Texas MD Anderson Cancer Center, Houston, United States
    Competing interests
    The authors declare that no competing interests exist.
  22. Paola A Guerrero

    Department of Pathology, University of Texas MD Anderson Cancer Center, Houston, United States
    Competing interests
    The authors declare that no competing interests exist.
  23. Surinder Batra

    University of Nebraska Medical Center, Omaha, United States
    Competing interests
    The authors declare that no competing interests exist.
  24. Michael Goggins

    Johns Hopkins University, Baltimore, United States
    Competing interests
    The authors declare that no competing interests exist.
  25. Ulrich Steidl

    Albert Einstein College of Medicine, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  26. John Greally

    Albert Einstein College of Medicine, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-6069-7960
  27. Beamon Agarwal

    GenomeRxUs LLC, Secane, United States
    Competing interests
    The authors declare that no competing interests exist.
  28. Kith Pradhan

    Albert Einstein College of Medicine, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  29. Debabrata Banerjee

    Rutgers University, New Brunswick, United States
    Competing interests
    The authors declare that no competing interests exist.
  30. Deepak Nagrath

    Biointerfaces Institute, University of Michigan, Ann Arbor, United States
    For correspondence
    dnagrath@umich.edu
    Competing interests
    The authors declare that no competing interests exist.
  31. Anirban Maitra

    Department of Pathology, University of Texas MD Anderson Cancer Center, Houston, United States
    For correspondence
    AMaitra@mdanderson.org
    Competing interests
    The authors declare that no competing interests exist.
  32. Amit Verma

    Albert Einstein College of Medicine, New York, United States
    For correspondence
    amit.verma@einstein.yu.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-7592-7693

Funding

Einstein Training Program in Stem Cell Research (C34874GG)

  • Tushar D Bhagat

National Cancer Institute (T32 CA200561)

  • Dagny Von Ahrens

National Cancer Institute (R01CA227622)

  • Deepak Nagrath

National Cancer Institute (R01CA222251)

  • Deepak Nagrath

National Cancer Institute (R01CA204969)

  • Deepak Nagrath

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 no. 20181208) protocols of the Albert Einstein College of Medicine.

Reviewing Editor

  1. Ralph DeBerardinis, UT Southwestern Medical Center, United States

Publication history

  1. Received: July 29, 2019
  2. Accepted: October 27, 2019
  3. Accepted Manuscript published: October 30, 2019 (version 1)
  4. Accepted Manuscript updated: November 1, 2019 (version 2)

Copyright

© 2019, Bhagat 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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