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

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. 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.

SUBMITTER: Apiz Saab JJ

PROVIDER: S-EPMC10260022 | biostudies-literature | 2023 May

REPOSITORIES: biostudies-literature

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

Apiz Saab Juan J JJ Dzierozynski Lindsey N LN Jonker Patrick B PB AminiTabrizi Roya R Shah Hardik H Menjivar Rosa Elena RE Scott Andrew J AJ Nwosu Zeribe C ZC Zhu Zhou Z Chen Riona N RN Oh Moses M Sheehan Colin C Wahl Daniel R DR Pasca di Magliano Marina M Lyssiotis Costas A CA Macleod Kay F KF Weber Christopher R CR Muir Alexander A

eLife 20230531

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 characte ...[more]

PMID: 37254839

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

Publications

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

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