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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Podrobná bibliografia
Vydané v:	Cell metabolism Ročník 29; číslo 6; s. 1390
Hlavní autori:	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
Médium:	Journal Article
Jazyk:	English
Vydavateľské údaje:	United States 04.06.2019
Predmet:	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
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Shrnutí:	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.
Bibliografia:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	1932-7420 1932-7420
DOI:	10.1016/j.cmet.2019.02.001