Quantification of microenvironmental metabolites in murine cancers reveals determinants of tumor nutrient availability
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.
Data availability
Source data files detailing the concentrations of each metabolite in each sample are included for all figures. We have also deposited this information and the raw mass spectra in Metabolomics Workbench (http://www.metabolomicsworkbench.org/) as project ID: PR000750.
Article and author information
Author details
Funding
National Cancer Institute (R01CA168653)
- Matthew G Vander Heiden
National Cancer Institute (F32CA210421)
- Laura V Danai
- Alexander Muir
Stand Up To Cancer
- Mark R Sullivan
- Laura V Danai
- Dan Y Gui
- Matthew G Vander Heiden
- Alexander Muir
Howard Hughes Medical Institute
- Mark R Sullivan
- Laura V Danai
- Dan Y Gui
- Matthew G Vander Heiden
- Alexander Muir
Ludwig Institute for Cancer Research
- Mark R Sullivan
- Laura V Danai
- Dan Y Gui
- Matthew G Vander Heiden
- Alexander Muir
Lustgarten Foundation
- Mark R Sullivan
- Laura V Danai
- Dan Y Gui
- Matthew G Vander Heiden
- Alexander Muir
Koch Institute for Integrative Cancer Research (Koch Institute Graduate Fellowship)
- Mark R Sullivan
National Cancer Institute (R01CA201276)
- Matthew G Vander Heiden
National Cancer Institute (P30CA1405141)
- Matthew G Vander Heiden
National Cancer Institute (F32CA213810)
- Laura V Danai
- Alexander Muir
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: This study was performed in accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals. All animals experiments were performed using protocols (#1115-110-18) that were approved by the MIT Committee on Animal Care (IACUC). All surgeries were performed using isoflurane anesthesia administered by vaporizer and every effort was made to minimize suffering.
Copyright
© 2019, Sullivan et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Further reading
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In healthy cells, cyclin D1 is expressed during the G1 phase of the cell cycle, where it activates CDK4 and CDK6. Its dysregulation is a well-established oncogenic driver in numerous human cancers. The cancer-related function of cyclin D1 has been primarily studied by focusing on the phosphorylation of the retinoblastoma (RB) gene product. Here, using an integrative approach combining bioinformatic analyses and biochemical experiments, we show that GTSE1 (G-Two and S phases expressed protein 1), a protein positively regulating cell cycle progression, is a previously unrecognized substrate of cyclin D1–CDK4/6 in tumor cells overexpressing cyclin D1 during G1 and subsequent phases. The phosphorylation of GTSE1 mediated by cyclin D1–CDK4/6 inhibits GTSE1 degradation, leading to high levels of GTSE1 across all cell cycle phases. Functionally, the phosphorylation of GTSE1 promotes cellular proliferation and is associated with poor prognosis within a pan-cancer cohort. Our findings provide insights into cyclin D1’s role in cell cycle control and oncogenesis beyond RB phosphorylation.
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