期刊
CELL METABOLISM
卷 29, 期 6, 页码 1390-+出版社
CELL PRESS
DOI: 10.1016/j.cmet.2019.02.001
关键词
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资金
- Pancreatic Cancer UK
- NCI [1K08CA234222]
- Sky Foundation
- Cancer Research UK
- Cancer Center Support Grant [P30CA046592, U01 CA224145]
- American Cancer Society
- Pancreatic Cancer Action Network/AACR [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]
- Agilent ACT-UR grant mechanism
- Charles Woodson Research Fund
- UM Pediatric Brain Tumor Initiative
- [UL1TR000433]
- [T32CA009676]
- [F32CA228328]
- [T32GM113900]
- [T32DK094775]
- [T32AI007413]
- [DK097153]
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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