Pancreatic tumors exhibit myeloid-driven amino acid stress and upregulate arginine biosynthesis
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 canc...
| Main Authors: | , , , , , , , , , , , , , , , , , |
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| Formato: | Artigo |
| Idioma: | English |
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eLife Sciences Publications Ltd
2023-05-01
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| Colecção: | eLife |
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| Acesso em linha: | https://elifesciences.org/articles/81289 |
| _version_ | 1827927955059245056 |
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| author | Juan J Apiz Saab Lindsey N Dzierozynski Patrick B Jonker Roya AminiTabrizi Hardik Shah Rosa Elena Menjivar Andrew J Scott Zeribe C Nwosu Zhou Zhu Riona N Chen Moses Oh Colin Sheehan Daniel R Wahl Marina Pasca di Magliano Costas A Lyssiotis Kay F Macleod Christopher R Weber Alexander Muir |
| author_facet | Juan J Apiz Saab Lindsey N Dzierozynski Patrick B Jonker Roya AminiTabrizi Hardik Shah Rosa Elena Menjivar Andrew J Scott Zeribe C Nwosu Zhou Zhu Riona N Chen Moses Oh Colin Sheehan Daniel R Wahl Marina Pasca di Magliano Costas A Lyssiotis Kay F Macleod Christopher R Weber Alexander Muir |
| author_sort | Juan J Apiz Saab |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-03-13T06:01:29Z |
| format | Article |
| id | doaj.art-c5f718ce140e4a6fa50f1ed1f45d288d |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-03-13T06:01:29Z |
| publishDate | 2023-05-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-c5f718ce140e4a6fa50f1ed1f45d288d2023-06-12T15:17:51ZengeLife Sciences Publications LtdeLife2050-084X2023-05-011210.7554/eLife.81289Pancreatic tumors exhibit myeloid-driven amino acid stress and upregulate arginine biosynthesisJuan J Apiz Saab0https://orcid.org/0000-0002-4799-9291Lindsey N Dzierozynski1https://orcid.org/0000-0001-5775-5429Patrick B Jonker2https://orcid.org/0000-0002-5074-3035Roya AminiTabrizi3Hardik Shah4Rosa Elena Menjivar5Andrew J Scott6https://orcid.org/0000-0002-0835-4888Zeribe C Nwosu7Zhou Zhu8Riona N Chen9Moses Oh10Colin Sheehan11Daniel R Wahl12Marina Pasca di Magliano13Costas A Lyssiotis14Kay F Macleod15https://orcid.org/0000-0002-8995-4155Christopher R Weber16Alexander Muir17https://orcid.org/0000-0003-3811-3054Ben May Department for Cancer Research, University of Chicago, Chicago, United StatesBen May Department for Cancer Research, University of Chicago, Chicago, United StatesBen May Department for Cancer Research, University of Chicago, Chicago, United StatesMetabolomics Platform, Comprehensive Cancer Center, University of Chicago, Chicago, United StatesMetabolomics Platform, Comprehensive Cancer Center, University of Chicago, Chicago, United StatesCellular and Molecular Biology Program, University of Michigan-Ann Arbor, Ann Arbor, United StatesDepartment of Radiation Oncology, University of Michigan, Ann Arbor, United StatesDepartment of Molecular and Integrative Physiology, University of Michigan-Ann Arbor, Ann Arbor, United StatesBen May Department for Cancer Research, University of Chicago, Chicago, United StatesBen May Department for Cancer Research, University of Chicago, Chicago, United StatesBen May Department for Cancer Research, University of Chicago, Chicago, United StatesBen May Department for Cancer Research, University of Chicago, Chicago, United StatesDepartment of Radiation Oncology, University of Michigan, Ann Arbor, United StatesCellular and Molecular Biology Program, University of Michigan-Ann Arbor, Ann Arbor, United StatesDepartment of Molecular and Integrative Physiology, University of Michigan-Ann Arbor, Ann Arbor, United StatesBen May Department for Cancer Research, University of Chicago, Chicago, United StatesDepartment of Pathology, University of Chicago, Chicago, United StatesBen May Department for Cancer Research, University of Chicago, Chicago, United StatesNutrient 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.https://elifesciences.org/articles/81289metabolismtumor microenvironmentamino acid homeostasisargininenutrient stress |
| spellingShingle | Juan J Apiz Saab Lindsey N Dzierozynski Patrick B Jonker Roya AminiTabrizi Hardik Shah Rosa Elena Menjivar Andrew J Scott Zeribe C Nwosu Zhou Zhu Riona N Chen Moses Oh Colin Sheehan Daniel R Wahl Marina Pasca di Magliano Costas A Lyssiotis Kay F Macleod Christopher R Weber Alexander Muir Pancreatic tumors exhibit myeloid-driven amino acid stress and upregulate arginine biosynthesis eLife metabolism tumor microenvironment amino acid homeostasis arginine nutrient stress |
| title | Pancreatic tumors exhibit myeloid-driven amino acid stress and upregulate arginine biosynthesis |
| title_full | Pancreatic tumors exhibit myeloid-driven amino acid stress and upregulate arginine biosynthesis |
| title_fullStr | Pancreatic tumors exhibit myeloid-driven amino acid stress and upregulate arginine biosynthesis |
| title_full_unstemmed | Pancreatic tumors exhibit myeloid-driven amino acid stress and upregulate arginine biosynthesis |
| title_short | Pancreatic tumors exhibit myeloid-driven amino acid stress and upregulate arginine biosynthesis |
| title_sort | pancreatic tumors exhibit myeloid driven amino acid stress and upregulate arginine biosynthesis |
| topic | metabolism tumor microenvironment amino acid homeostasis arginine nutrient stress |
| url | https://elifesciences.org/articles/81289 |
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