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Pancreatic tumors activate arginine biosynthesis to adapt to myeloid-driven amino acid stress

Juan J. Apiz-Saab, Lindsey N. Dzierozynski, Patrick B. Jonker, Zhou Zhu, Riona N. Chen, Moses Oh, Colin Sheehan, Kay F. Macleod, Christopher R. Weber, View ORCID ProfileAlexander Muir
doi: https://doi.org/10.1101/2022.06.21.497008
Juan J. Apiz-Saab
1Ben May Department for Cancer Research, University of Chicago, Chicago, Illinois, USA
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Lindsey N. Dzierozynski
1Ben May Department for Cancer Research, University of Chicago, Chicago, Illinois, USA
3Department of Medicine, Johns Hopkins University School of Medicine and the Bloomberg School of Public Health, Baltimore, MD 21287
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Patrick B. Jonker
1Ben May Department for Cancer Research, University of Chicago, Chicago, Illinois, USA
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Zhou Zhu
1Ben May Department for Cancer Research, University of Chicago, Chicago, Illinois, USA
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Riona N. Chen
1Ben May Department for Cancer Research, University of Chicago, Chicago, Illinois, USA
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Moses Oh
1Ben May Department for Cancer Research, University of Chicago, Chicago, Illinois, USA
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Colin Sheehan
1Ben May Department for Cancer Research, University of Chicago, Chicago, Illinois, USA
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Kay F. Macleod
1Ben May Department for Cancer Research, University of Chicago, Chicago, Illinois, USA
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Christopher R. Weber
2Department of Pathology, The University of Chicago, Chicago, United States
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Alexander Muir
1Ben May Department for Cancer Research, University of Chicago, Chicago, Illinois, USA
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  • ORCID record for Alexander Muir
  • For correspondence: amuir@uchicago.edu
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Abstract

Nutrient stress in the tumor microenvironment requires cancer cells to adopt adaptive metabolic programs to maintain 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 (Sullivan et al., 2019a). Here, we develop Tumor Interstitial Fluid Medium (TIFM), a cell culture medium that contains nutrient levels representative of the PDAC microenvironment, enabling study of PDAC metabolism under physiological nutrition. We show that PDAC cells cultured in TIFM, compared to standard laboratory models, adopt a cellular state more similar to PDAC cells in tumors. Further, using the TIFM model we identified arginine biosynthesis as a metabolic adaptation PDAC cells engage to cope with microenvironmental arginine starvation driven by myeloid cells in PDAC tumors. Altogether, these data show 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 and enable the discovery of novel cancer metabolic phenotypes.

Competing Interest Statement

The authors have declared no competing interest.

Footnotes

  • https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE199163

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC 4.0 International license.
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Posted June 25, 2022.
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Pancreatic tumors activate arginine biosynthesis to adapt to myeloid-driven amino acid stress
Juan J. Apiz-Saab, Lindsey N. Dzierozynski, Patrick B. Jonker, Zhou Zhu, Riona N. Chen, Moses Oh, Colin Sheehan, Kay F. Macleod, Christopher R. Weber, Alexander Muir
bioRxiv 2022.06.21.497008; doi: https://doi.org/10.1101/2022.06.21.497008
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Pancreatic tumors activate arginine biosynthesis to adapt to myeloid-driven amino acid stress
Juan J. Apiz-Saab, Lindsey N. Dzierozynski, Patrick B. Jonker, Zhou Zhu, Riona N. Chen, Moses Oh, Colin Sheehan, Kay F. Macleod, Christopher R. Weber, Alexander Muir
bioRxiv 2022.06.21.497008; doi: https://doi.org/10.1101/2022.06.21.497008

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