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Cell Metab. 2019 Feb 21. pii: S1550-4131(19)30065-8. doi: 10.1016/j.cmet.2019.02.001. [Epub ahead of print]

Macrophage-Released Pyrimidines Inhibit Gemcitabine Therapy in Pancreatic Cancer.

Author information

1
Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI 48109, USA.
2
Cancer Research UK, Beatson Institute, Glasgow G61 1BD, UK.
3
West of Scotland Pancreatic Unit, Glasgow Royal Infirmary, Glasgow G61 1QH, UK; Institute of Cancer Sciences, University of Glasgow, Glasgow G61 1QH, UK.
4
Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI 48109, USA; University of Michigan Rogel Cancer Center, University of Michigan, Ann Arbor, MI 48109, USA.
5
Department of Surgery, University of Michigan, Ann Arbor, MI 48109, USA.
6
Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA.
7
University of Michigan Rogel Cancer Center, University of Michigan, Ann Arbor, MI 48109, USA; Department of Surgery, University of Michigan, Ann Arbor, MI 48109, USA.
8
Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI 48109, USA; University of Michigan Rogel Cancer Center, University of Michigan, Ann Arbor, MI 48109, USA; Department of Internal Medicine, Division of Gastroenterology and Hepatology, University of Michigan, Ann Arbor, MI 48109, USA.
9
Cancer Research UK, Beatson Institute, Glasgow G61 1BD, UK; Institute of Cancer Sciences, University of Glasgow, Glasgow G61 1QH, UK.
10
Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI 48109, USA; University of Michigan Rogel Cancer Center, University of Michigan, Ann Arbor, MI 48109, USA; Department of Internal Medicine, Division of Gastroenterology and Hepatology, University of Michigan, Ann Arbor, MI 48109, USA. Electronic address: clyssiot@med.umich.edu.

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.

KEYWORDS:

deoxycytidine; gemcitabine resistance; immunometabolism; macrophage; metabolic crosstalk; metabolomics; pancreatic cancer; pancreatic ductal adenocarcinoma; tumor microenvironment; tumor-associated macrophage

PMID:
30827862
DOI:
10.1016/j.cmet.2019.02.001

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