Quantification of Microenvironmental Metabolites in Murine Cancers Reveals Determinants of Tumor Nutrient Availability

Overview

Journal Elife

Specialty Biology

Date 2019 Apr 17

PMID 30990168

Citations 271

Authors

Mark R Sullivan

Laura V Danai

Caroline A Lewis

Sze Ham Chan

Dan Y Gui

Tenzin Kunchok

Emily A Dennstedt

Matthew G Vander Heiden

Alexander Muir

Affiliations

Soon will be listed here.

Abstract

Cancer cell metabolism is heavily influenced by microenvironmental factors, including nutrient availability. Therefore, knowledge of microenvironmental nutrient levels is essential to understand tumor metabolism. To measure the extracellular nutrient levels available to tumors, we utilized quantitative metabolomics methods to measure the absolute concentrations of >118 metabolites in plasma and tumor interstitial fluid, the extracellular fluid that perfuses tumors. Comparison of nutrient levels in tumor interstitial fluid and plasma revealed that the nutrients available to tumors differ from those present in circulation. Further, by comparing interstitial fluid nutrient levels between autochthonous and transplant models of murine pancreatic and lung adenocarcinoma, we found that tumor type, anatomical location and animal diet affect local nutrient availability. These data provide a comprehensive characterization of the nutrients present in the tumor microenvironment of widely used models of lung and pancreatic cancer and identify factors that influence metabolite levels in tumors.

Citing Articles

NLRP4 unlocks an NK/macrophages-centered ecosystem to suppress non-small cell lung cancer.

Meng Z, Li J, Wang H, Cao Z, Lu W, Niu X Biomark Res. 2025; 13(1):44.

PMID: 40087771 DOI: 10.1186/s40364-025-00756-4.

Deciphering Colorectal Cancer-Hepatocyte Interactions: A Multiomics Platform for Interrogation of Metabolic Crosstalk in the Liver-Tumor Microenvironment.

Nelson A, Reese L, Rono E, Queathem E, Qiu Y, McCluskey B Int J Mol Sci. 2025; 26(5).

PMID: 40076609 PMC: 11900982. DOI: 10.3390/ijms26051976.

Glycogen drives tumour initiation and progression in lung adenocarcinoma.

Clarke H, Hawkinson T, Shedlock C, Medina T, Ribas R, Wu L Nat Metab. 2025; .

PMID: 40069440 DOI: 10.1038/s42255-025-01243-8.

Interleukin-16 enhances anti-tumor immune responses by establishing a Th1 cell-macrophage crosstalk through reprogramming glutamine metabolism in mice.

Wen Z, Liu T, Xu X, Acharya N, Shen Z, Lu Y Nat Commun. 2025; 16(1):2362.

PMID: 40064918 PMC: 11893787. DOI: 10.1038/s41467-025-57603-1.

Myeloid cells: key players in tumor microenvironments.

Hua Q, Li Z, Weng Y, Wu Y, Zheng L Front Med. 2025; .

PMID: 40048137 DOI: 10.1007/s11684-025-1124-8.

References

SAUER L, Stayman 3rd J, Dauchy R . Amino acid, glucose, and lactic acid utilization in vivo by rat tumors. Cancer Res. 1982; 42(10):4090-7. View

Anastasiou D . Tumour microenvironment factors shaping the cancer metabolism landscape. Br J Cancer. 2016; 116(3):277-286. PMC: 5294476. DOI: 10.1038/bjc.2016.412. View

Siska P, Beckermann K, Mason F, Andrejeva G, Greenplate A, Sendor A . Mitochondrial dysregulation and glycolytic insufficiency functionally impair CD8 T cells infiltrating human renal cell carcinoma. JCI Insight. 2017; 2(12). PMC: 5470888. DOI: 10.1172/jci.insight.93411. View

Son J, Lyssiotis C, Ying H, Wang X, Hua S, Ligorio M . Glutamine supports pancreatic cancer growth through a KRAS-regulated metabolic pathway. Nature. 2013; 496(7443):101-5. PMC: 3656466. DOI: 10.1038/nature12040. View

DuFort C, DelGiorno K, Carlson M, Osgood R, Zhao C, Huang Z . Interstitial Pressure in Pancreatic Ductal Adenocarcinoma Is Dominated by a Gel-Fluid Phase. Biophys J. 2016; 110(9):2106-19. PMC: 4939548. DOI: 10.1016/j.bpj.2016.03.040. View

Wiig H, Aukland K, Tenstad O . Isolation of interstitial fluid from rat mammary tumors by a centrifugation method. Am J Physiol Heart Circ Physiol. 2002; 284(1):H416-24. DOI: 10.1152/ajpheart.00327.2002. View

Sayin V, LeBoeuf S, Singh S, Davidson S, Biancur D, Guzelhan B . Activation of the NRF2 antioxidant program generates an imbalance in central carbon metabolism in cancer. Elife. 2017; 6. PMC: 5624783. DOI: 10.7554/eLife.28083. View

Zaytouni T, Tsai P, Hitchcock D, DuBois C, Freinkman E, Lin L . Critical role for arginase 2 in obesity-associated pancreatic cancer. Nat Commun. 2017; 8(1):242. PMC: 5556090. DOI: 10.1038/s41467-017-00331-y. View

Haslene-Hox H, Oveland E, Berg K, Kolmannskog O, Woie K, Salvesen H . A new method for isolation of interstitial fluid from human solid tumors applied to proteomic analysis of ovarian carcinoma tissue. PLoS One. 2011; 6(4):e19217. PMC: 3082557. DOI: 10.1371/journal.pone.0019217. View

10.

Muir A, Vander Heiden M . The nutrient environment affects therapy. Science. 2018; 360(6392):962-963. PMC: 6368963. DOI: 10.1126/science.aar5986. View

11.

Yau E, Kummetha I, Lichinchi G, Tang R, Zhang Y, Rana T . Genome-Wide CRISPR Screen for Essential Cell Growth Mediators in Mutant KRAS Colorectal Cancers. Cancer Res. 2017; 77(22):6330-6339. PMC: 5690866. DOI: 10.1158/0008-5472.CAN-17-2043. View

12.

Ryan C, Bajrami I, Lord C . Synthetic Lethality and Cancer - Penetrance as the Major Barrier. Trends Cancer. 2018; 4(10):671-683. DOI: 10.1016/j.trecan.2018.08.003. View

13.

Jackson E, Olive K, Tuveson D, Bronson R, Crowley D, Brown M . The differential effects of mutant p53 alleles on advanced murine lung cancer. Cancer Res. 2005; 65(22):10280-8. DOI: 10.1158/0008-5472.CAN-05-2193. View

14.

Wiig H, Swartz M . Interstitial fluid and lymph formation and transport: physiological regulation and roles in inflammation and cancer. Physiol Rev. 2012; 92(3):1005-60. DOI: 10.1152/physrev.00037.2011. View

15.

Morandi A, Giannoni E, Chiarugi P . Nutrient Exploitation within the Tumor-Stroma Metabolic Crosstalk. Trends Cancer. 2017; 2(12):736-746. DOI: 10.1016/j.trecan.2016.11.001. View

16.

Mayers J, Wu C, Clish C, Kraft P, Torrence M, Fiske B . Elevation of circulating branched-chain amino acids is an early event in human pancreatic adenocarcinoma development. Nat Med. 2014; 20(10):1193-1198. PMC: 4191991. DOI: 10.1038/nm.3686. View

17.

Geiger R, Rieckmann J, Wolf T, Basso C, Feng Y, Fuhrer T . L-Arginine Modulates T Cell Metabolism and Enhances Survival and Anti-tumor Activity. Cell. 2016; 167(3):829-842.e13. PMC: 5075284. DOI: 10.1016/j.cell.2016.09.031. View

18.

Sousa C, Biancur D, Wang X, Halbrook C, Sherman M, Zhang L . Pancreatic stellate cells support tumour metabolism through autophagic alanine secretion. Nature. 2016; 536(7617):479-83. PMC: 5228623. DOI: 10.1038/nature19084. View

19.

Uhlen M, Fagerberg L, Hallstrom B, Lindskog C, Oksvold P, Mardinoglu A . Proteomics. Tissue-based map of the human proteome. Science. 2015; 347(6220):1260419. DOI: 10.1126/science.1260419. View

20.

Koong A, Mehta V, Le Q, Fisher G, Terris D, Brown J . Pancreatic tumors show high levels of hypoxia. Int J Radiat Oncol Biol Phys. 2000; 48(4):919-22. DOI: 10.1016/s0360-3016(00)00803-8. View