Macrophage-released pyrimidines inhibit gemcitabine therapy in pancreatic cancer

Halbrook, C. J. et al. (2019) Macrophage-released pyrimidines inhibit gemcitabine therapy in pancreatic cancer. Cell Metabolism, 29(6), 1390-1399.e6. (doi: 10.1016/j.cmet.2019.02.001) (PMID:30827862) (PMCID:PMC6602533)

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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.

Item Type:Articles
Additional Information:C.J.H. was supported by UL1TR000433, T32CA009676, and F32CA228328; L.L. by Pancreatic Cancer UK; S.K. by T32GM113900; B.S.N. by T32CA009676 and T32DK094775; J.S. by NCI 1K08CA234222; H.C.C. by the Sky Foundation; J.P.M. by Cancer Research UK; H.S.H. by T32AI007413; C.A.L., H.C.C., and M.P.d.M. by a Cancer Center Support Grant (P30CA046592) and U01 CA224145; M.P.d.M. by the American Cancer Society; C.A.L. by the 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), and the AACR (17-20-01-LYSS). Metabolomics studies were supported by DK097153, an Agilent ACT-UR grant mechanism, the Charles Woodson Research Fund, and the UM Pediatric Brain Tumor Initiative.
Keywords:Deoxycytidine, gemcitabine resistance, immunometabolism, macrophage, metabolic crosstalk, metabolomics, pancreatic cancer, pancreatic ductal adenocarcinoma, tumor microenvironment, tumor-associated macrophage.
Glasgow Author(s) Enlighten ID:Dreyer, Dr Stephan and Biankin, Professor Andrew and Morton, Professor Jen and Chang, Professor David
Authors: Halbrook, C. J., Pontious, C., Kovalenko, I., Lapienyte, L., Dreyer, S., Lee, H.-J., Thurston, G., Zhang, Y., Lazarus, J., Sajjakulnukit, P., Hong, H. S., Kremer, D. M., Nelson, B. S., Kemp, S., Zhang, L., Chang, D., Biankin, A., Shi, J., Frankel, T. L., Crawford, H. C., Morton, J. P., Pasca di Magliano, M., and Lyssiotis, C. A.
College/School:College of Medical Veterinary and Life Sciences > School of Cancer Sciences
Journal Name:Cell Metabolism
ISSN (Online):1932-7420
Published Online:28 February 2019

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