Affiliation:
1. Ben May Department for Cancer Research, University of Chicago
2. Metabolomics Platform, Comprehensive Cancer Center, University of Chicago
3. Cellular and Molecular Biology Program, University of Michigan-Ann Arbor
4. Department of Radiation Oncology, University of Michigan
5. Department of Molecular and Integrative Physiology, University of Michigan-Ann Arbor
6. Department of Pathology, University of Chicago
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.
Funder
National Center for Advancing Translational Sciences
American Cancer Society
University of Chicago Comprehensive Cancer Center
Pancreatic Cancer Action Network
Brinson Foundation
Cancer Research Foundation
Ludwig Center for Metastasis Research
National Cancer Institute
National Institutes of Health
National Institute of Neurological Disorders and Stroke
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
Publisher
eLife Sciences Publications, Ltd
Subject
General Immunology and Microbiology,General Biochemistry, Genetics and Molecular Biology,General Medicine,General Neuroscience
Cited by
19 articles.
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