Pancreatic tumors exhibit myeloid-driven amino acid stress and upregulate arginine biosynthesis
- University of Chicago, United States
- University of Michigan-Ann Arbor, United States
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
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Metabolomics dataMetabolomics Workbench, PR001627.
Article and author information
Author details
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
- 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
- Received: June 23, 2022
- Preprint posted: June 25, 2022 (view preprint)
- Accepted: May 25, 2023
- Accepted Manuscript published: May 31, 2023 (version 1)
- 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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Pancreatic tumors exhibit myeloid-driven amino acid stress and upregulate arginine biosynthesis
eLife 12:e81289.
https://doi.org/10.7554/eLife.81289
Further reading
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- Biochemistry and Chemical Biology
- Cancer Biology
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.
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- Biochemistry and Chemical Biology
- Cancer Biology
Studying the nutrient composition immediately surrounding pancreatic cancer cells provides new insights into their metabolic properties and how they can evade the immune system to promote disease progression.
