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.
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.
Metrics
-
- 7,009
- views
-
- 1,229
- downloads
-
- 65
- 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)
Dissecting cell type-specific metabolism in pancreatic ductal adenocarcinoma
eLife 9:e56782.
https://doi.org/10.7554/eLife.56782
Further reading
-
- Cancer Biology
Tumor neoantigen peptide vaccines hold potential for boosting cancer immunotherapy, yet efficiently co-delivering peptides and adjuvants to antigen-presenting cells in vivo remains challenging. Virus-like particle (VLP), which is a kind of multiprotein structure organized as virus, can deliver therapeutic substances into cells and stimulate immune response. However, the weak targeted delivery of VLP in vivo and its susceptibility to neutralization by antibodies hinder their clinical applications. Here, we first designed a novel protein carrier using the mammalian-derived capsid protein PEG10, which can self-assemble into endogenous VLP (eVLP) with high protein loading and transfection efficiency. Then, an engineered tumor vaccine, named ePAC, was developed by packaging genetically encoded neoantigen into eVLP with further modification of CpG-ODN on its surface to serve as an adjuvant and targeting unit to dendritic cells (DCs). Significantly, ePAC can efficiently target and transport neoantigens to DCs, and promote DCs maturation to induce neoantigen-specific T cells. Moreover, in mouse orthotopic liver cancer and humanized mouse tumor models, ePAC combined with anti-TIM-3 exhibited remarkable antitumor efficacy. Overall, these results support that ePAC could be safely utilized as cancer vaccines for antitumor therapy, showing significant potential for clinical translation.
-
- Cancer Biology
In T-cell acute lymphoblastic leukemia (T-ALL), more than 50% of cases display autoactivation of Notch1 signaling, leading to oncogenic transformation. We have previously identified a specific chemovar of Cannabis that induces apoptosis by preventing Notch1 maturation in leukemia cells. Here, we isolated three cannabinoids from this chemovar that synergistically mimic the effects of the whole extract. Two were previously known, cannabidiol (CBD) and cannabidivarin (CBDV), whereas the third cannabinoid, which we termed 331-18A, was identified and fully characterized in this study. We demonstrated that these cannabinoids act through cannabinoid receptor type 2 and TRPV1 to activate the integrated stress response pathway by depleting intracellular Ca2+. This is followed by increased mRNA and protein expression of ATF4, CHOP, and CHAC1, which is hindered by inhibiting the upstream initiation factor eIF2α. The increased abundance of CHAC1 prevents Notch1 maturation, thereby reducing the levels of the active Notch1 intracellular domain, and consequently decreasing cell viability and increasing apoptosis. Treatment with the three isolated molecules resulted in reduced tumor size and weight in vivo and slowed leukemia progression in mice models. Altogether, this study elucidated the mechanism of action of three distinct cannabinoids in modulating the Notch1 pathway, and constitutes an important step in the establishment of a new therapy for treating NOTCH1-mutated diseases and cancers such as T-ALL.
