Macrophage-Released Pyrimidines Inhibit Gemcitabine Therapy in Pancreatic Cancer
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Abstract
Pancreatic ductal adenocarcinoma (PDA) is characterized by abundant infiltration of tumor-associated macrophages (TAMs). TAMs have been reported to drive resistance to gemcitabine, a frontline chemotherapy in PDA, though the mechanism of this resistance remains unclear. Profiling metabolite exchange, we demonstrate that macrophages programmed by PDA cells release a spectrum of pyrimidine species. These include deoxycytidine, which inhibits gemcitabine through molecular competition at the level of drug uptake and metabolism. Accordingly, genetic or pharmacological depletion of TAMs in murine models of PDA sensitizes these tumors to gemcitabine. Consistent with this, patients with low macrophage burden demonstrate superior response to gemcitabine treatment. Together, these findings provide insights into the role of macrophages in pancreatic cancer therapy and have potential to inform the design of future treatments. Additionally, we report that pyrimidine release is a general function of alternatively activated macrophage cells, suggesting an unknown physiological role of pyrimidine exchange by immune cells.
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PDAC-induced macrophage polarization causes macrophages to release deoxycytidine, which competitively inhibits gemcitabine and lowers its therapeutic efficacy.
“PDAC-induced macrophage polarization causes the macrophages to release deoxycytidine, which competitively inhibits the chemotherapeutic agent gemcitabine and lowers its therapeutic efficacy (112).”
From Metabolic reprogramming and cancer progression (2020) · cites this paper as [112]
Metabolic interactions between cancer cells and the microenvironment can promote therapy resistance.
“In some cases, metabolic interactions between cancer cells and the microenvironment promote therapy resistance.”
From Metabolic reprogramming and cancer progression (2020) · cites this paper as [112]
PDAC cells can obtain GlcNAc through N-acetylglucosamine kinase salvage from matrix components, including hyaluronic acid.
“PDAC cells can also obtain GlcNAC through N-acetylglucosamine kinase salvage from matrix components256, including hyaluronic acid257”
From Pancreatic cancer: Advances and challenges (2023) · cites this paper as [257]
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- Authors
- Halbrook, C. J., Pontious, C., Kovalenko, I., Lapienyte, L., Dreyer, S., Lee, H.-J., Thurston, G., Zhang, Y., Lazarus, J., Sajjakulnukit, P., Hong, H. S., Kremer, D. M., Nelson, B. S., Kemp, S., Zhang, L., Chang, D., Biankin, A., Shi, J., Frankel, T. L., Crawford, H. C., Morton, J. P., Pasca di Magliano, M., & Lyssiotis, C. A.
- Affiliations
- University of Michigan (US)
- Cancer Research UK Scotland Institute (GB)
- Glasgow Royal Infirmary (GB)
- Corresponding author
- Lyssiotis, Costas A.
- ORCID
- Halbrook, Christopher J.
- Pontious, Corbin
- Kovalenko, Ilya
- Dreyer, Stephan
- Lee, Ho-Joon
- Zhang, Yaqing
- Lazarus, Jenny
- Sajjakulnukit, Peter
- Hong, Hanna S.
- Kremer, Daniel M.
- Nelson, Barbara S.
- Kemp, Samantha
- Zhang, Li
- Chang, David
- Biankin, Andrew
- Shi, Jiaqi
- Frankel, Timothy L.
- Crawford, Howard C.
- Morton, Jennifer P.
- Lyssiotis, Costas A.
- Venue
- Cell Metabolism
- Publisher
- Elsevier BV
- Published
- 2019-06
- Volume
- 29
- Issue
- 6
- Pages
- 1390-1399.e6
- ISSN
- 1550-4131 (ISSN-L)
- PMC
- PMC6602533
- OpenAlex
- W2950705205
- Cited by
- 419
- References
- 43
- Citations by year
- 2026: 29 · 2025: 47 · 2024: 48 · 2023: 72 · 2022: 59 · 2021: 78 · 2020: 63 · 2019: 23
- FWCI
- 22.48
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell Metabolism (publishedVersion)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- ENLIGHTEN (Jurnal Bimbingan dan Konseling Islam) (submittedVersion, cc-by-sa)
- Funders
- Pancreatic Cancer UK (UL1TR000433, T32CA009676, F32CA228328, T32GM113900, T32DK094775)
- NCI (1K08CA234222)
- Sky Foundation
- Cancer Research UK (T32AI007413)
- Cancer Center Support Grant (P30CA046592, U01 CA224145)
- American Cancer Society
- Pancreatic Cancer Action Network (13-70-25-LYSS)
- Damon Runyon Cancer Research Foundation (DFS-09-14)
- V Foundation for Cancer Research (V2016-009)
- Sidney Kimmel Foundation for Cancer Research (SKF-16-005)
- AACR (17-20-01-LYSS)
- Charles Woodson Research Fund (DK097153)
- UM Pediatric Brain Tumor Initiative
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Immune cells in cancer
- Health Sciences › Medicine › Oncology › Pancreatic and Hepatic Oncology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Physiology › Adenosine and Purinergic Signaling
- Keywords
- pancreatic ductal adenocarcinoma, tumor-associated macrophages, gemcitabine resistance, deoxycytidine, drug competition, macrophage depletion, alternative activation, chemosensitivity, metabolite exchange
- MeSH terms
- RAW 264.7 Cells, Gemcitabine, Animals, Cells, Cultured, Deoxycytidine, Female, Humans, Macrophages, Male, Mice, Inbred C57BL, Mice, Transgenic, Pancreatic Neoplasms, Pyrimidines, Drug Resistance, Neoplasm, Carcinoma, Pancreatic Ductal, Xenograft Model Antitumor Assays, Mice
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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