Quantification of microenvironmental metabolites in murine cancers reveals determinants of tumor nutrient availability
- Massachusetts Institute of Technology, United States
- University of Chicago, United States
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
Matthew G Vander Heiden
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.
Metrics
-
- 20,821
- views
-
- 3,308
- downloads
-
- 434
- citations
Views, downloads and citations are aggregated across all versions of this paper published by eLife.
Download links
A two-part list of links to download the article, or parts of the article, in various formats.
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
Quantification of microenvironmental metabolites in murine cancers reveals determinants of tumor nutrient availability
eLife 8:e44235.
https://doi.org/10.7554/eLife.44235
Further reading
-
- Biochemistry and Chemical Biology
The protein ligase Connectase can be used to fuse proteins to small molecules, solid carriers, or other proteins. Compared to other protein ligases, it offers greater substrate specificity, higher catalytic efficiency, and catalyzes no side reactions. However, its reaction is reversible, resulting in only 50% fusion product from two equally abundant educts. Here, we present a simple method to reliably obtain 100% fusion product in 1:1 conjugation reactions. This method is efficient for protein-protein or protein-peptide fusions at the N- or C-termini. It enables the generation of defined and completely labeled antibody conjugates with one fusion partner on each chain. The reaction requires short incubation times with small amounts of enzyme and is effective even at low substrate concentrations and at low temperatures. With these characteristics, it presents a valuable new tool for bioengineering.
-
- Biochemistry and Chemical Biology
- Structural Biology and Molecular Biophysics
African trypanosomes are the causative agents of neglected tropical diseases affecting both humans and livestock. Disease control is highly challenging due to an increasing number of drug treatment failures. African trypanosomes are extracellular, blood-borne parasites that mainly rely on glycolysis for their energy metabolism within the mammalian host. Trypanosomal glycolytic enzymes are therefore of interest for the development of trypanocidal drugs. Here, we report the serendipitous discovery of a camelid single-domain antibody (sdAb aka Nanobody) that selectively inhibits the enzymatic activity of trypanosomatid (but not host) pyruvate kinases through an allosteric mechanism. By combining enzyme kinetics, biophysics, structural biology, and transgenic parasite survival assays, we provide a proof-of-principle that the sdAb-mediated enzyme inhibition negatively impacts parasite fitness and growth.
