Dissecting cell type-specific metabolism in pancreatic ductal adenocarcinoma
- Massachusetts Institute of Technology, United States
- University of Massachusetts, Amherst, United States
- Harvard Medical School, United States
- Cold Spring Harbor Laboratory, United States
- University of Cambridge, United Kingdom
Abstract
Tumors are composed of many different cell types including cancer cells, fibroblasts, and immune cells. Dissecting functional metabolic differences between cell types within a mixed population can be challenging due to the rapid turnover of metabolites relative to the time needed to isolate cells. To overcome this challenge, we traced isotope-labeled nutrients into macromolecules that turn over more slowly than metabolites. This approach was used to assess differences between cancer cell and fibroblast metabolism in murine pancreatic cancer organoid-fibroblast co-cultures and tumors. Pancreatic cancer cells exhibited increased pyruvate carboxylation relative to fibroblasts, and this flux depended on both pyruvate carboxylase and malic enzyme 1 activity. Consequently, expression of both enzymes in cancer cells was necessary for organoid and tumor growth, demonstrating that dissecting the metabolism of specific cell populations within heterogeneous systems can identify dependencies that may not be evident from studying isolated cells in culture or bulk tissue.
Data availability
All data generated or analyzed during this study are included in the manuscript and supporting files.
Article and author information
Author details
Nicholas J Matheson
Matthew G Vander Heiden
Funding
Damon Runyon Cancer Research Foundation (DRG-2241-15)
- Allison N Lau
National Cancer Institute (U54CA163109)
- Vasilena Gocheva
Human Frontiers Science Program (LT000195/2015-L)
- Giulia Biffi
EMBO (ALTF 1203-2014)
- Giulia Biffi
Howard Hughes Medical Institute
- Tyler Jacks
- Matthew G Vander Heiden
MRC (CSF MR/P008801/1)
- Nicholas J Matheson
NHSBT (WPA15-02)
- Nicholas J Matheson
NIHR Cambridge BRC
- Nicholas J Matheson
National Institutes of Health (R01CA211184)
- Omer Yilmaz
National Institutes of Health (R01CA034992)
- Omer Yilmaz
Lustgarten Foundation
- Matthew G Vander Heiden
Damon Runyon Cancer Research Foundation (DRG-2367-19)
- Sharanya Sivanand
Stand Up To Cancer
- Matthew G Vander Heiden
MIT Center for Precision Cancer Medicine
- Matthew G Vander Heiden
Ludwig Center at MIT
- Tyler Jacks
- Matthew G Vander Heiden
Emerald Foundation
- Matthew G Vander Heiden
National Cancer Institute (R01CA168653)
- Matthew G Vander Heiden
National Cancer Institute (R01CA201276)
- Matthew G Vander Heiden
National Cancer Institute (R35CA242379)
- Matthew G Vander Heiden
National Cancer Institute (P30CA14051)
- Matthew G Vander Heiden
Damon Runyon Cancer Research Foundation (DRG-2299-17)
- Evan C Lien
National Cancer Institute (K99CA234221)
- Allison N Lau
National Institutes of Health (T32GM007287)
- Zhaoqi Li
- Kiera M Sapp
Jane Coffin Childs Memorial Fund for Medical Research
- Alicia M Darnell
- Vasilena Gocheva
Swedish Foundation for Strategic Research
- Raphael Ferreira
Knut and Alice Wallenberg Foundation
- Raphael Ferreira
Barbro Osher Pro Suecia Foundation
- Raphael Ferreira
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: All animal studies were approved by the MIT Committee on Animal Care under protocol #0119-001-22.
Reviewing Editor
- Ralph DeBerardinis, UT Southwestern Medical Center, United States
Publication history
- Received: March 9, 2020
- Accepted: July 9, 2020
- Accepted Manuscript published: July 10, 2020 (version 1)
- Version of Record published: August 5, 2020 (version 2)
Copyright
© 2020, Lau 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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Dissecting cell type-specific metabolism in pancreatic ductal adenocarcinoma
eLife 9:e56782.
https://doi.org/10.7554/eLife.56782
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