Abstract

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 (M. R. Sullivan, Danai, et al., 2019). 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.

Data availability

Sequencing data from Figures 1 and 3 have been deposited in GEO under accession code GSE199163: https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE199163. Source data files with measured metabolite concentrations and isotopic labeling patterns are provided for Figures 2 and 4. Raw mass spectra data from relevant experiments have been deposited in NIH sponsored Metabolomics Workbench repository (Sud et al., 2016) under Project ID PR001627: https://www.metabolomicsworkbench.org/data/DRCCMetadata.php?Mode=Project&ProjectID=PR001627

The following data sets were generated

Article and author information

Author details

  1. Juan J Apiz Saab

    en May Department for Cancer Research, University of Chicago, Chicago, United States
    Competing interests
    No competing interests declared.
  2. Lindsey N Dzierozynski

    en May Department for Cancer Research, University of Chicago, Chicago, United States
    Competing interests
    No competing interests declared.
  3. Patrick B Jonker

    en May Department for Cancer Research, University of Chicago, Chicago, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-5074-3035
  4. Roya AminiTabrizi

    Metabolomics Platform, University of Chicago, Chicago, United States
    Competing interests
    No competing interests declared.
  5. Hardik Shah

    Metabolomics Platform, University of Chicago, Chicago, United States
    Competing interests
    No competing interests declared.
  6. Rosa Elena Menjivar

    Cellular and Molecular Biology Program, University of Michigan-Ann Arbor, Ann Arbor, United States
    Competing interests
    No competing interests declared.
  7. Andrew J Scott

    Department of Molecular and Integrative Physiology, University of Michigan-Ann Arbor, Ann Arbor, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-0835-4888
  8. Zeribe C Nwosu

    Department of Molecular and Integrative Physiology, University of Michigan-Ann Arbor, Ann Arbor, United States
    Competing interests
    No competing interests declared.
  9. Zhou Zhu

    Ben May Department for Cancer Research, University of Chicago, Chicago, United States
    Competing interests
    No competing interests declared.
  10. Riona N Chen

    Ben May Department for Cancer Research, University of Chicago, Chicago, United States
    Competing interests
    No competing interests declared.
  11. Moses Oh

    Ben May Department for Cancer Research, University of Chicago, Chicago, United States
    Competing interests
    No competing interests declared.
  12. Colin Sheehan

    Ben May Department for Cancer Research, University of Chicago, Chicago, United States
    Competing interests
    No competing interests declared.
  13. Daniel R Wahl

    Department of Radiation Oncology, University of Michigan-Ann Arbor, Ann Arbor, United States
    Competing interests
    No competing interests declared.
  14. Marina Pasca di Magliano

    Cellular and Molecular Biology Program, University of Michigan-Ann Arbor, Ann Arbor, United States
    Competing interests
    No competing interests declared.
  15. Costas A Lyssiotis

    Department of Molecular and Integrative Physiology, University of Michigan-Ann Arbor, Ann Arbor, United States
    Competing interests
    Costas A Lyssiotis, has received consulting fees from Astellas Pharmaceuticals, Odyssey Therapeutics, and T-Knife Therapeutics, and is an inventor on patents pertaining to Kras regulated metabolic pathways, redox control pathways in pancreatic cancer, and targeting the GOT1-pathway as a therapeutic approach (US Patent No: 2015126580-A1, 05/07/2015; US Patent No: 20190136238, 05/09/2019; International Patent No: WO2013177426-A2, 04/23/2015)..
  16. Kay F Macleod

    Ben May Department for Cancer Research, University of Chicago, Chicago, United States
    Competing interests
    Kay F Macleod, Reviewing editor, eLife.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-8995-4155
  17. Christopher R Weber

    Department of Pathology, University of Chicago, Chicago, United States
    Competing interests
    No competing interests declared.
  18. Alexander Muir

    Ben May Department for Cancer Research, University of Chicago, Chicago, United States
    For correspondence
    amuir@uchicago.edu
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-3811-3054

Funding

National Center for Advancing Translational Sciences (5UL1TR002389-04)

  • Alexander Muir

National Institutes of Health (T32-GM007315)

  • Rosa Elena Menjivar

National Institutes of Health (T32-HD007505)

  • Rosa Elena Menjivar

National Cancer Institute (F31-CA257533)

  • Rosa Elena Menjivar

National Cancer Institute (K99CA267176)

  • Zeribe C Nwosu

National Institutes of Health (R25GM143298)

  • Zeribe C Nwosu

National Cancer Institute (R37CA237421)

  • Costas A Lyssiotis

National Cancer Institute (P30CA046592)

  • Costas A Lyssiotis

National Cancer Institute (K08CA234416)

  • Daniel R Wahl

National Cancer Institute (R37CA258346)

  • Daniel R Wahl

NINDS (R01NS129123)

  • Daniel R Wahl

American Cancer Society (IRG-16-222-56)

  • Alexander Muir

Damon Runyon Cancer Research Foundation

  • Daniel R Wahl

Sontag Foundation

  • Daniel R Wahl

Ivy Glioblastoma Foundation

  • Daniel R Wahl

Alex's Lemonade Stand Foundation for Childhood Cancer

  • Daniel R Wahl

ChadTough Foundation

  • Daniel R Wahl

Forbes Institute for Cancer Discovery

  • Daniel R Wahl

University of Chicago Comprehensive Cancer Center (P30 CA14599)

  • Alexander Muir

Pancreatic Cancer Action Network (2020 Career Development Award)

  • Alexander Muir

Brinson Foundation

  • Alexander Muir

Cancer Research Foundation

  • Alexander Muir

Ludwig Center for Metastasis Research

  • Alexander Muir

National Cancer Institute (R01 CA200310)

  • Kay F Macleod

National Cancer Institute (T32 CA009594)

  • Lindsey N Dzierozynski
  • Patrick B Jonker
  • Colin Sheehan

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

Reviewing Editor

  1. Gina M DeNicola, Moffitt Cancer Center, United States

Ethics

Animal experimentation: Animal experiments were approved by the University of Chicago Institutional Animal Care and Use Committee (IACUC, Protocol #72587) and performed in strict accordance with the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health (Bethesda, MD).

Human subjects: Human histology samples were obtained under approval by the Institutional Review Boards at the University of Chicago (IRB 17-0437).

Version history

  1. Received: June 23, 2022
  2. Preprint posted: June 25, 2022 (view preprint)
  3. Accepted: May 25, 2023
  4. Accepted Manuscript published: May 31, 2023 (version 1)
  5. Version of Record published: June 12, 2023 (version 2)

Copyright

© 2023, Apiz Saab 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. Juan J Apiz Saab
  2. Lindsey N Dzierozynski
  3. Patrick B Jonker
  4. Roya AminiTabrizi
  5. Hardik Shah
  6. Rosa Elena Menjivar
  7. Andrew J Scott
  8. Zeribe C Nwosu
  9. Zhou Zhu
  10. Riona N Chen
  11. Moses Oh
  12. Colin Sheehan
  13. Daniel R Wahl
  14. Marina Pasca di Magliano
  15. Costas A Lyssiotis
  16. Kay F Macleod
  17. Christopher R Weber
  18. Alexander Muir
(2023)
Pancreatic tumors exhibit myeloid-driven amino acid stress and upregulate arginine biosynthesis
eLife 12:e81289.
https://doi.org/10.7554/eLife.81289

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https://doi.org/10.7554/eLife.81289

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