Macrophage-Released Pyrimidines Inhibit Gemcitabine Therapy in Pancreatic Cancer

被引：306

作者：

Halbrook, Christopher J. ^{[1
]}

Pontious, Corbin ^{[1
]}

Kovalenko, Ilya ^{[1
]}

Lapienyte, Laura ^{[2
]}

Dreyer, Stephan ^{[3
,4
]}

Lee, Ho-Joon ^{[1
,5
]}

Thurston, Galloway ^{[1
]}

Zhang, Yaqing ^{[6
]}

Lazarus, Jenny ^{[6
]}

Sajjakulnukit, Peter ^{[1
]}

Hong, Hanna S. ^{[1
]}

Kremer, Daniel M. ^{[1
]}

Nelson, Barbara S. ^{[1
]}

Kemp, Samantha ^{[7
]}

Zhang, Li ^{[1
]}

Chang, David ^{[3
,4
]}

Biankin, Andrew ^{[3
,4
]}

Shi, Jiaqi ^{[7
]}

Frankel, Timothy L. ^{[5
,6
]}

Crawford, Howard C. ^{[1
,5
,8
]}

Morton, Jennifer P. ^{[2
,4
]}

di Magliano, Marina Pasca ^{[5
,6
]}

Lyssiotis, Costas A. ^{[1
,5
,8
]}

机构：

[1] Univ Michigan, Dept Mol & Integrat Physiol, Ann Arbor, MI 48109 USA

[2] Canc Res UK, Beatson Inst, Glasgow G61 1BD, Lanark, Scotland

[3] Glasgow Royal Infirm, West Scotland Pancreat Unit, Glasgow G61 1QH, Lanark, Scotland

[4] Univ Glasgow, Inst Canc Sci, Glasgow G61 1QH, Lanark, Scotland

[5] Univ Michigan, Rogel Canc Ctr, Ann Arbor, MI 48109 USA

[6] Univ Michigan, Dept Surg, Ann Arbor, MI 48109 USA

[7] Univ Michigan, Dept Pathol, Ann Arbor, MI 48109 USA

[8] Univ Michigan, Dept Internal Med, Div Gastroenterol & Hepatol, Ann Arbor, MI 48109 USA

来源：

CELL METABOLISM | 2019年 / 29卷 / 06期

关键词：

TUMOR-INFILTRATING MACROPHAGES; METABOLISM; CELLS; IDENTIFICATION; FOLFIRINOX; DELIVERY; SUPPORT; GROWTH;

D O I：

10.1016/j.cmet.2019.02.001

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

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.

引用

页码：1390 / +

页数：16

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