1. Biochemistry and Chemical Biology
  2. Cancer Biology

Quantification of microenvironmental metabolites in murine cancers reveals determinants of tumor nutrient availability

  1. Mark R Sullivan
  2. Laura V Danai
  3. Caroline A Lewis
  4. Sze Ham Chan
  5. Dan Y Gui
  6. Tenzin Kunchok
  7. Emily A Dennstedt
  8. Matthew G Vander Heiden  Is a corresponding author
  9. Alexander Muir  Is a corresponding author
  1. Massachusetts Institute of Technology, United States
  2. University of Chicago, United States
https://doi.org/10.7554/eLife.44235
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Cite this article
  1. Mark R Sullivan
  2. Laura V Danai
  3. Caroline A Lewis
  4. Sze Ham Chan
  5. Dan Y Gui
  6. Tenzin Kunchok
  7. Emily A Dennstedt
  8. Matthew G Vander Heiden
  9. Alexander Muir
(2019)
Quantification of microenvironmental metabolites in murine cancers reveals determinants of tumor nutrient availability
eLife 8:e44235.
https://doi.org/10.7554/eLife.44235
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Abstract

Cancer cell metabolism is heavily influenced by microenvironmental factors, including nutrient availability. Therefore, knowledge of microenvironmental nutrient levels is essential to understand tumor metabolism. To measure the extracellular nutrient levels available to tumors, we utilized quantitative metabolomics methods to measure the absolute concentrations of >118 metabolites in plasma and tumor interstitial fluid, the extracellular fluid that perfuses tumors. Comparison of nutrient levels in tumor interstitial fluid and plasma revealed that the nutrients available to tumors differ from those present in circulation. Further, by comparing interstitial fluid nutrient levels between autochthonous and transplant models of murine pancreatic and lung adenocarcinoma, we found that tumor type, anatomical location and animal diet affect local nutrient availability. These data provide a comprehensive characterization of the nutrients present in the tumor microenvironment of widely used models of lung and pancreatic cancer and identify factors that influence metabolite levels in tumors.

Data availability

Source data files detailing the concentrations of each metabolite in each sample are included for all figures. We have also deposited this information and the raw mass spectra in Metabolomics Workbench (http://www.metabolomicsworkbench.org/) as project ID: PR000750.

The following data sets were generated

Article and author information

Author details

  1. Mark R Sullivan

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

  2. Laura V Danai

    Department of Biology, Massachusetts Institute of Technology, Cambridge, United States
    Competing interests
    Laura V Danai, has applied for patents for therapeutic strategies to target cancer metabolism.(US Patent App. 15/890,220).

  3. Caroline A Lewis

    Whitehead Institute for Biomedical Research, Massachusetts Institute of Technology, Cambridge, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-1787-5084

  4. Sze Ham Chan

    Whitehead Institute for Biomedical Research, Massachusetts Institute of Technology, Cambridge, United States
    Competing interests
    No competing interests declared.

  5. Dan Y Gui

    Department of Biology, Massachusetts Institute of Technology, Cambridge, United States
    Competing interests
    Dan Y Gui, has applied for patents for therapeutic strategies to target cancer metabolism.(US Patent App. 15/890,220).

  6. Tenzin Kunchok

    Whitehead Institute for Biomedical Research, Massachusetts Institute of Technology, Cambridge, United States
    Competing interests
    No competing interests declared.

  7. Emily A Dennstedt

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

  8. 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, has applied for patents for therapeutic strategies to target cancer metabolism. (US Patent App. 15/890,220). Also on the scientific advisory board of Agios Pharmaceuticals, Aeglea Biotherapeutics, and Auron Therapeutics, which seek to exploit altered metabolism for therapy. Reviewing editor, eLife.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-6702-4192

  9. Alexander Muir

    Ben May Department for Cancer Research, University of Chicago, Chicago, United States
    For correspondence
    amuir@uchicago.edu
    Competing interests
    Alexander Muir, has applied for patents for therapeutic strategies to target cancer metabolism.(US Patent App. 15/890,220).
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-3811-3054

Funding

National Cancer Institute (R01CA168653)

  • Matthew G Vander Heiden

National Cancer Institute (F32CA210421)

  • Laura V Danai
  • Alexander Muir

Stand Up To Cancer

  • Mark R Sullivan
  • Laura V Danai
  • Dan Y Gui
  • Matthew G Vander Heiden
  • Alexander Muir

Howard Hughes Medical Institute

  • Mark R Sullivan
  • Laura V Danai
  • Dan Y Gui
  • Matthew G Vander Heiden
  • Alexander Muir

Ludwig Institute for Cancer Research

  • Mark R Sullivan
  • Laura V Danai
  • Dan Y Gui
  • Matthew G Vander Heiden
  • Alexander Muir

Lustgarten Foundation

  • Mark R Sullivan
  • Laura V Danai
  • Dan Y Gui
  • Matthew G Vander Heiden
  • Alexander Muir

Koch Institute for Integrative Cancer Research (Koch Institute Graduate Fellowship)

  • Mark R Sullivan

National Cancer Institute (R01CA201276)

  • Matthew G Vander Heiden

National Cancer Institute (P30CA1405141)

  • Matthew G Vander Heiden

National Cancer Institute (F32CA213810)

  • Laura V Danai
  • Alexander Muir

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 accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals. All animals experiments were performed using protocols (#1115-110-18) that were approved by the MIT Committee on Animal Care (IACUC). All surgeries were performed using isoflurane anesthesia administered by vaporizer and every effort was made to minimize suffering.

Copyright

© 2019, Sullivan 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. Mark R Sullivan
  2. Laura V Danai
  3. Caroline A Lewis
  4. Sze Ham Chan
  5. Dan Y Gui
  6. Tenzin Kunchok
  7. Emily A Dennstedt
  8. Matthew G Vander Heiden
  9. Alexander Muir
(2019)
Quantification of microenvironmental metabolites in murine cancers reveals determinants of tumor nutrient availability
eLife 8:e44235.
https://doi.org/10.7554/eLife.44235

Share this article

https://doi.org/10.7554/eLife.44235

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Further reading

    1. Biochemistry and Chemical Biology
    2. Cancer Biology

    Pancreatic tumors exhibit myeloid-driven amino acid stress and upregulate arginine biosynthesis

    Juan J Apiz Saab, Lindsey N Dzierozynski ... Alexander Muir
    Research Advance Updated

    Nutrient stress in the tumor microenvironment requires cancer cells to adopt adaptive metabolic programs for survival and proliferation. Therefore, knowledge of microenvironmental nutrient levels and how cancer cells cope with such nutrition is critical to understand the metabolism underpinning cancer cell biology. Previously, we performed quantitative metabolomics of the interstitial fluid (the local perfusate) of murine pancreatic ductal adenocarcinoma (PDAC) tumors to comprehensively characterize nutrient availability in the microenvironment of these tumors. Here, we develop Tumor Interstitial Fluid Medium (TIFM), a cell culture medium that contains nutrient levels representative of the PDAC microenvironment, enabling us to study PDAC metabolism ex vivo under physiological nutrient conditions. We show that PDAC cells cultured in TIFM adopt a cellular state closer to that of PDAC cells present in tumors compared to standard culture models. Further, using the TIFM model, we found arginine biosynthesis is active in PDAC and allows PDAC cells to maintain levels of this amino acid despite microenvironmental arginine depletion. We also show that myeloid derived arginase activity is largely responsible for the low levels of arginine in PDAC tumors. Altogether, these data indicate that nutrient availability in tumors is an important determinant of cancer cell metabolism and behavior, and cell culture models that incorporate physiological nutrient availability have improved fidelity to in vivo systems and enable the discovery of novel cancer metabolic phenotypes.