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Published May 31, 2023 | Version v1
Journal article Open

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

Creators

  • 1. University of Chicago
  • 2. University of Michigan

Description

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.

Data availability

Sequencing data from Figures 1 and 3 have been deposited in GEO under accession code 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.

The following data sets were generated:

Saab JJMuir A (2022) NCBI Gene Expression Omnibus ID GSE199163. Transcriptomic profiling of mouse PDAC cells flow sorted from an orthotopic murine tumor model, cultured in standard cell culture nutrients or in physiological nutrients. https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE199163

Saab JJ (2023) Metabolomics Workbench ID PR001627. Metabolomics data. https://www.metabolomicsworkbench.org/data/DRCCMetadata.php?Mode=Project&ProjectID=PR001627

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Additional details

Identifiers

DOI
10.7554/eLife.81289
Other
oai:uchicago.tind.io:9803

Related works

Cites
https://doi.org/10.1101/2022.06.21.497008 (URL)

Funding

National Center for Advancing Translational Sciences
5UL1TR002389-04
American Cancer Society
IRG-16-222-56
University of Chicago Comprehensive Cancer Center
P30 CA14599
Pancreatic Cancer Action Network
2020 Career Development Award
Brinson Foundation
Cancer Research Foundation
Ludwig Center for Metastasis Research
National Cancer Institute
R01 CA200310
National Cancer Institute
T32 CA009594
National Institutes of Health
T32-GM007315
National Institutes of Health
T32-HD007505
National Cancer Institute
F31-CA257533
National Cancer Institute
K99CA267176
National Institutes of Health
R25GM143298
National Cancer Institute
R37CA237421
National Cancer Institute
P30CA046592
National Cancer Institute
K08CA234416
National Cancer Institute
R37CA258346
National Institute of Neurological Disorders and Stroke
R01NS129123
Damon Runyon Cancer Research Foundation
Sontag Foundation
Ivy Glioblastoma Foundation
Alex's Lemonade Stand Foundation for Childhood Cancer
ChadTough Foundation
Forbes Institute for Cancer Discovery
National Cancer Institute
NIH/NCI F32CA260735-01

UChicago Information

Division(s)
Biological Sciences Division
Department(s)
Ben May Department for Cancer Research, Pathology
Center(s) or Institute(s)
Comprehensive Cancer Center