Macrophage-Released Pyrimidines Inhibit Gemcitabine Therapy in Pancreatic Cancer

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...

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Bibliographic Details
Published in:Cell metabolism Vol. 29; no. 6; p. 1390
Main Authors: Halbrook, Christopher J, Pontious, Corbin, Kovalenko, Ilya, Lapienyte, Laura, Dreyer, Stephan, Lee, Ho-Joon, Thurston, Galloway, 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, Pasca di Magliano, Marina, Lyssiotis, Costas A
Format: Journal Article
Language:English
Published: United States 04.06.2019
Subjects:
Animals
Carcinoma, Pancreatic Ductal - drug therapy
Carcinoma, Pancreatic Ductal - metabolism
Carcinoma, Pancreatic Ductal - pathology
Cells, Cultured
Deoxycytidine - analogs & derivatives
Deoxycytidine - therapeutic use
Drug Resistance, Neoplasm - drug effects
Female
Gemcitabine
Humans
Macrophages - metabolism
Male
Mice
Mice, Inbred C57BL
Mice, Transgenic
Pancreatic Neoplasms - drug therapy
Pancreatic Neoplasms - metabolism
Pancreatic Neoplasms - pathology
Pyrimidines - metabolism
Pyrimidines - pharmacology
RAW 264.7 Cells
Xenograft Model Antitumor Assays
pancreatic cancer
deoxycytidine
gemcitabine resistance
immunometabolism
metabolomics
macrophage
tumor-associated macrophage
tumor microenvironment
metabolic crosstalk
pancreatic ductal adenocarcinoma
ISSN:1932-7420, 1932-7420
Online Access:Get more information
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Summary: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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ISSN:1932-7420
1932-7420
DOI:10.1016/j.cmet.2019.02.001