Dissecting cell type-specific metabolism in pancreatic ductal adenocarcinoma

  1. Allison N Lau
  2. Zhaoqi Li
  3. Laura V Danai
  4. Anna M Westermark
  5. Alicia M Darnell
  6. Raphael Ferreira
  7. Vasilena Gocheva
  8. Sharanya Sivanand
  9. Evan C Lien
  10. Kiera M Sapp
  11. Jared R Mayers
  12. Giulia Biffi
  13. Christopher R Chin
  14. Shawn M Davidson
  15. David A Tuveson
  16. Tyler Jacks
  17. Nicholas J Matheson
  18. Omer Yilmaz
  19. Matthew G Vander Heiden  Is a corresponding author
  1. Massachusetts Institute of Technology, United States
  2. University of Massachusetts, Amherst, United States
  3. Harvard Medical School, United States
  4. Cold Spring Harbor Laboratory, United States
  5. University of Cambridge, United Kingdom

Abstract

Tumors are composed of many different cell types including cancer cells, fibroblasts, and immune cells. Dissecting functional metabolic differences between cell types within a mixed population can be challenging due to the rapid turnover of metabolites relative to the time needed to isolate cells. To overcome this challenge, we traced isotope-labeled nutrients into macromolecules that turn over more slowly than metabolites. This approach was used to assess differences between cancer cell and fibroblast metabolism in murine pancreatic cancer organoid-fibroblast co-cultures and tumors. Pancreatic cancer cells exhibited increased pyruvate carboxylation relative to fibroblasts, and this flux depended on both pyruvate carboxylase and malic enzyme 1 activity. Consequently, expression of both enzymes in cancer cells was necessary for organoid and tumor growth, demonstrating that dissecting the metabolism of specific cell populations within heterogeneous systems can identify dependencies that may not be evident from studying isolated cells in culture or bulk tissue.

Data availability

All data generated or analyzed during this study are included in the manuscript and supporting files.

Article and author information

Author details

  1. Allison N Lau

    Department of Biology, Massachusetts Institute of Technology, Cambridge, United States
    Competing interests
    No competing interests declared.
  2. Zhaoqi Li

    Department of Biology, Massachusetts Institute of Technology, Cambridge, United States
    Competing interests
    No competing interests declared.
  3. Laura V Danai

    Department of Biochemistry and Molecular Biology, University of Massachusetts, Amherst, Amherst, MA, United States
    Competing interests
    No competing interests declared.
  4. Anna M Westermark

    Department of Biology, Massachusetts Institute of Technology, Cambridge, United States
    Competing interests
    No competing interests declared.
  5. Alicia M Darnell

    Department of Biology, Massachusetts Institute of Technology, Cambridge, United States
    Competing interests
    No competing interests declared.
  6. Raphael Ferreira

    Department of Genetics, Harvard Medical School, Boston, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-9881-6232
  7. Vasilena Gocheva

    Department of Biology, Massachusetts Institute of Technology, Cambridge, United States
    Competing interests
    No competing interests declared.
  8. Sharanya Sivanand

    Department of Biology, Massachusetts Institute of Technology, Cambridge, United States
    Competing interests
    No competing interests declared.
  9. Evan C Lien

    Department of Biology, Massachusetts Institute of Technology, Cambridge, United States
    Competing interests
    No competing interests declared.
  10. Kiera M Sapp

    Department of Biology, Massachusetts Institute of Technology, Cambridge, United States
    Competing interests
    No competing interests declared.
  11. Jared R Mayers

    Department of Biology, Massachusetts Institute of Technology, Cambridge, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-8607-1787
  12. Giulia Biffi

    Cancer and Molecular Biology, Cold Spring Harbor Laboratory, Cold Spring Harbor, United States
    Competing interests
    No competing interests declared.
  13. Christopher R Chin

    Department of Biology, Massachusetts Institute of Technology, Cambridge, United States
    Competing interests
    No competing interests declared.
  14. Shawn M Davidson

    Department of Biology, Massachusetts Institute of Technology, Cambridge, United States
    Competing interests
    No competing interests declared.
  15. David A Tuveson

    Cancer and Molecular Biology, Cold Spring Harbor Laboratory, Cold Spring Harbor, United States
    Competing interests
    No competing interests declared.
  16. Tyler Jacks

    Koch Institute for Integrative Cancer Research and the Department of Biology, Massachusetts Institute of Technology, Cambridge, United States
    Competing interests
    Tyler Jacks, T.J. is a member of the Board of Directors of Amgen and Thermo Fisher Scientific, is a co-Founder of Dragonfly Therapeutics and T2 Biosystems, and is a scientific advisor of SQZ Biotech, and Skyhawk Therapeutics..
  17. Nicholas J Matheson

    Department of Medicine, University of Cambridge, Cambridge, United Kingdom
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-3318-1851
  18. Omer Yilmaz

    Biology, Massachusetts Institute of Technology, Cambridge, United States
    Competing interests
    No competing interests declared.
  19. Matthew G Vander Heiden

    Department of Biology, Massachusetts Institute of Technology, Cambridge, United States
    For correspondence
    mvh@mit.edu
    Competing interests
    Matthew G Vander Heiden, Reviewing editor, eLife; is a scientific advisor for Agios Pharmaceuticals, Aeglea Biotherapeutics, iTeos Therapeutics, and Auron Therapeutics.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-6702-4192

Funding

Damon Runyon Cancer Research Foundation (DRG-2241-15)

  • Allison N Lau

National Cancer Institute (U54CA163109)

  • Vasilena Gocheva

Human Frontiers Science Program (LT000195/2015-L)

  • Giulia Biffi

EMBO (ALTF 1203-2014)

  • Giulia Biffi

Howard Hughes Medical Institute

  • Tyler Jacks
  • Matthew G Vander Heiden

MRC (CSF MR/P008801/1)

  • Nicholas J Matheson

NHSBT (WPA15-02)

  • Nicholas J Matheson

NIHR Cambridge BRC

  • Nicholas J Matheson

National Institutes of Health (R01CA211184)

  • Omer Yilmaz

National Institutes of Health (R01CA034992)

  • Omer Yilmaz

Lustgarten Foundation

  • Matthew G Vander Heiden

Damon Runyon Cancer Research Foundation (DRG-2367-19)

  • Sharanya Sivanand

Stand Up To Cancer

  • Matthew G Vander Heiden

MIT Center for Precision Cancer Medicine

  • Matthew G Vander Heiden

Ludwig Center at MIT

  • Tyler Jacks
  • Matthew G Vander Heiden

Emerald Foundation

  • Matthew G Vander Heiden

National Cancer Institute (R01CA168653)

  • Matthew G Vander Heiden

National Cancer Institute (R01CA201276)

  • Matthew G Vander Heiden

National Cancer Institute (R35CA242379)

  • Matthew G Vander Heiden

National Cancer Institute (P30CA14051)

  • Matthew G Vander Heiden

Damon Runyon Cancer Research Foundation (DRG-2299-17)

  • Evan C Lien

National Cancer Institute (K99CA234221)

  • Allison N Lau

National Institutes of Health (T32GM007287)

  • Zhaoqi Li
  • Kiera M Sapp

Jane Coffin Childs Memorial Fund for Medical Research

  • Alicia M Darnell
  • Vasilena Gocheva

Swedish Foundation for Strategic Research

  • Raphael Ferreira

Knut and Alice Wallenberg Foundation

  • Raphael Ferreira

Barbro Osher Pro Suecia Foundation

  • Raphael Ferreira

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 studies were approved by the MIT Committee on Animal Care under protocol #0119-001-22.

Reviewing Editor

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

Publication history

  1. Received: March 9, 2020
  2. Accepted: July 9, 2020
  3. Accepted Manuscript published: July 10, 2020 (version 1)
  4. Version of Record published: August 5, 2020 (version 2)

Copyright

© 2020, Lau 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. Allison N Lau
  2. Zhaoqi Li
  3. Laura V Danai
  4. Anna M Westermark
  5. Alicia M Darnell
  6. Raphael Ferreira
  7. Vasilena Gocheva
  8. Sharanya Sivanand
  9. Evan C Lien
  10. Kiera M Sapp
  11. Jared R Mayers
  12. Giulia Biffi
  13. Christopher R Chin
  14. Shawn M Davidson
  15. David A Tuveson
  16. Tyler Jacks
  17. Nicholas J Matheson
  18. Omer Yilmaz
  19. Matthew G Vander Heiden
(2020)
Dissecting cell type-specific metabolism in pancreatic ductal adenocarcinoma
eLife 9:e56782.
https://doi.org/10.7554/eLife.56782

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