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.
Reviewing Editor
- Ralph DeBerardinis, UT Southwestern Medical Center, United States
Ethics
Animal experimentation: All animal studies were approved by the MIT Committee on Animal Care under protocol #0119-001-22.
Version 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
Further reading
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- Cancer Biology
- Genetics and Genomics
Enhancers are critical for regulating tissue-specific gene expression, and genetic variants within enhancer regions have been suggested to contribute to various cancer-related processes, including therapeutic resistance. However, the precise mechanisms remain elusive. Using a well-defined drug-gene pair, we identified an enhancer region for dihydropyrimidine dehydrogenase (DPD, DPYD gene) expression that is relevant to the metabolism of the anti-cancer drug 5-fluorouracil (5-FU). Using reporter systems, CRISPR genome-edited cell models, and human liver specimens, we demonstrated in vitro and vivo that genotype status for the common germline variant (rs4294451; 27% global minor allele frequency) located within this novel enhancer controls DPYD transcription and alters resistance to 5-FU. The variant genotype increases recruitment of the transcription factor CEBPB to the enhancer and alters the level of direct interactions between the enhancer and DPYD promoter. Our data provide insight into the regulatory mechanisms controlling sensitivity and resistance to 5-FU.
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- Cancer Biology
- Epidemiology and Global Health
Background:
Age is the most important risk factor for cancer, but aging rates are heterogeneous across individuals. We explored a new measure of aging-Phenotypic Age (PhenoAge)-in the risk prediction of site-specific and overall cancer.
Methods:
Using Cox regression models, we examined the association of Phenotypic Age Acceleration (PhenoAgeAccel) with cancer incidence by genetic risk group among 374,463 participants from the UK Biobank. We generated PhenoAge using chronological age and nine biomarkers, PhenoAgeAccel after subtracting the effect of chronological age by regression residual, and an incidence-weighted overall cancer polygenic risk score (CPRS) based on 20 cancer site-specific polygenic risk scores (PRSs).
Results:
Compared with biologically younger participants, those older had a significantly higher risk of overall cancer, with hazard ratios (HRs) of 1.22 (95% confidence interval, 1.18–1.27) in men, and 1.26 (1.22–1.31) in women, respectively. A joint effect of genetic risk and PhenoAgeAccel was observed on overall cancer risk, with HRs of 2.29 (2.10–2.51) for men and 1.94 (1.78–2.11) for women with high genetic risk and older PhenoAge compared with those with low genetic risk and younger PhenoAge. PhenoAgeAccel was negatively associated with the number of healthy lifestyle factors (Beta = –1.01 in men, p<0.001; Beta = –0.98 in women, p<0.001).
Conclusions:
Within and across genetic risk groups, older PhenoAge was consistently related to an increased risk of incident cancer with adjustment for chronological age and the aging process could be retarded by adherence to a healthy lifestyle.
Funding:
This work was supported by the National Natural Science Foundation of China (82230110, 82125033, 82388102 to GJ; 82273714 to MZ); and the Excellent Youth Foundation of Jiangsu Province (BK20220100 to MZ).
