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Macrophage-Released Pyrimidines Inhibit Gemcitabine Therapy in Pancreatic Cancer
- Source :
- Cell Metab
- Publication Year :
- 2019
-
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.
- Subjects :
- Male
0301 basic medicine
Physiology
medicine.medical_treatment
Mice, Transgenic
Tumor-associated macrophage
Deoxycytidine
Article
Mice
03 medical and health sciences
chemistry.chemical_compound
0302 clinical medicine
Immune system
Pancreatic cancer
medicine
Animals
Humans
Molecular Biology
Cells, Cultured
Chemotherapy
Tumor microenvironment
Innate immune system
Chemistry
Macrophages
Cell Biology
medicine.disease
Xenograft Model Antitumor Assays
Gemcitabine
Mice, Inbred C57BL
Pancreatic Neoplasms
RAW 264.7 Cells
030104 developmental biology
Pyrimidines
Drug Resistance, Neoplasm
Cancer research
Female
030217 neurology & neurosurgery
Carcinoma, Pancreatic Ductal
medicine.drug
Subjects
Details
- Language :
- English
- Database :
- OpenAIRE
- Journal :
- Cell Metab
- Accession number :
- edsair.doi.dedup.....ff61df064d9d0abfc9f4434aa89511c8