Dissecting cell-type-specific metabolism in pancreatic ductal adenocarcinoma

Lau, A. N., Li, Z., Danai, L. V., Westermark, A. M., Darnell, A. M., Ferreira, R., Gocheva, V., Sivanand, S., Lien, E. C., Sapp, K. M., Mayers, J. R., Biffi, G., Chin, C. R., Davidson, S. M., Tuveson, D. A., Jacks, T., Matheson, N. J., Yilmaz, O., Vander Heiden, M. G. (July 2020) Dissecting cell-type-specific metabolism in pancreatic ductal adenocarcinoma. Elife, 9. ISSN 2050-084x

URL: https://pubmed.ncbi.nlm.nih.gov/32648540/
DOI: 10.7554/eLife.56782

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. Tumors contain a mixture of many different types of cells, including cancer cells and non-cancer cells. The interactions between these two groups of cells affect how the cancer cells use nutrients, which, in turn, affects how fast these cells grow and divide. Furthermore, different cell types may use nutrients in diverse ways to make other molecules – known as metabolites – that the cell needs to survive. Fibroblasts are a subset of non-cancer cells that are typically found in tumors and can help them form. Separating fibroblasts from cancer cells in a tumor takes a lot longer than the chemical reactions in each cell of the tumor that produce and use up nutrients, also known as the cell’s metabolism. Therefore, measuring the levels of glucose (the sugar that is the main energy source for cells) and other metabolites in each tumor cell after separating them does not necessarily provide accurate information about the tumor cell’s metabolism. This makes it difficult to study how cancer cells and fibroblasts use nutrients differently. Lau et al. have developed a strategy to study the metabolism of cancer cells and fibroblasts in tumors. Mice with tumors in their pancreas were provided glucose that had been labelled using biochemical techniques. As expected, when the cell processed the glucose, the label was transferred into metabolites that got used up very quickly. But the label also became incorporated into larger, more stable molecules, such as proteins. Unlike the small metabolites, these larger molecules do not change in the time it takes to separate the cancer cells from the fibroblasts. Lau et al. sorted cells from whole pancreatic tumors and analyzed large, stable molecules that can incorporate the label from glucose in cancer cells and fibroblasts. The experiments showed that, in cancer cells, these molecules were more likely to have labeling patterns that are characteristic of two specific enzymes called pyruvate carboxylase and malic enzyme 1. This suggests that these enzymes are more active in cancer cells. Lau et al. also found that pancreatic cancer cells needed these two enzymes to metabolize glucose and to grow into large tumors. Pancreatic cancer is one of the most lethal cancers and current therapies offer limited benefit to many patients. Therefore, it is important to develop new drugs to treat this disease. Understanding how cancer cells and non-cancer cells in pancreatic tumors use nutrients differently is important for developing drugs that only target cancer cells. eng

Item Type: Paper
Additional Information: 2050-084x Lau, Allison N Orcid: 0000-0003-4250-7355 Li, Zhaoqi Danai, Laura V Westermark, Anna M Darnell, Alicia M Ferreira, Raphael Orcid: 0000-0001-9881-6232 Gocheva, Vasilena Sivanand, Sharanya Lien, Evan C Sapp, Kiera M Mayers, Jared R Orcid: 0000-0002-8607-1787 Biffi, Giulia Chin, Christopher R Davidson, Shawn M Tuveson, David A Jacks, Tyler Matheson, Nicholas J Orcid: 0000-0002-3318-1851 Yilmaz, Omer Vander Heiden, Matthew G Orcid: 0000-0002-6702-4192 K99 CA234221/CA/NCI NIH HHS/United States P30CA14051/CA/NCI NIH HHS/United States K99CA234221/CA/NCI NIH HHS/United States R01CA201276/CA/NCI NIH HHS/United States R35CA242379/CA/NCI NIH HHS/United States Altf 1203-2014/embo/ T32 GM007287/GM/NIGMS NIH HHS/United States Csf mr/p008801/1/mrc/ R01 CA168653/CA/NCI NIH HHS/United States DRG-2299-17/DRCRF/Damon Runyon Cancer Research Foundation/United States P30 CA014051/CA/NCI NIH HHS/United States DRG-2241-15/DRCRF/Damon Runyon Cancer Research Foundation/United States U54CA163109/CA/NCI NIH HHS/United States R01CA168653/CA/NCI NIH HHS/United States R01CA211184/NH/NIH HHS/United States R01CA034992/NH/NIH HHS/United States R01 CA201276/CA/NCI NIH HHS/United States U54 CA163109/CA/NCI NIH HHS/United States R35 CA242379/CA/NCI NIH HHS/United States LT000195/2015-L/Human Frontiers Science Program/ LT000195/2015-L/Human Frontier Science Program/ R01 CA034992/CA/NCI NIH HHS/United States R01 CA211184/CA/NCI NIH HHS/United States T32GM007287/NH/NIH HHS/United States Wpa15-02/nhsbt/ DRG-2367-19/DRCRF/Damon Runyon Cancer Research Foundation/United States Journal Article Elife. 2020 Jul 10;9:e56782. doi: 10.7554/eLife.56782.
Uncontrolled Keywords: Pdac cancer biology malic enzyme 1 metabolic heterogeneity mouse organoid culture pancreatic cancer pyruvate carboxylase interests declared, TJ TJ is a member of the Board of Directors of Amgen and Thermo Fisher Scientific, is a co-Founder of Dragonfly Therapeutics and T2 Biosystems, and is a scientific advisor of SQZ Biotech, and Skyhawk Therapeutics. MV Reviewing editor, eLife. MGVH is a member of the scientific advisory board member for Agios Pharmaceuticals, Aeglea Biotherapeutics, and iTeos Therapeutics, and a co-founder of Auron Therapeutics
Subjects: Investigative techniques and equipment > cell culture > cancer organoids
diseases & disorders > cancer > cancer types > pancreatic cancer
CSHL Authors:
Communities: CSHL labs > Tuveson lab
CSHL Cancer Center Program > Cellular Communication in Cancer Program
Depositing User: Matthew Dunn
Date: 10 July 2020
Date Deposited: 14 Dec 2020 16:29
Last Modified: 07 Jun 2021 16:08
PMCID: PMC7406355
Related URLs:
URI: https://repository.cshl.edu/id/eprint/39684

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