Dataset Information

Macrophage-Released Pyrimidines Inhibit Gemcitabine Therapy in Pancreatic Cancer.

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.

SUBMITTER: Halbrook CJ

PROVIDER: S-EPMC6602533 | biostudies-literature | 2019 Jun

REPOSITORIES: biostudies-literature

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Publications

Macrophage-Released Pyrimidines Inhibit Gemcitabine Therapy in Pancreatic Cancer.

Halbrook Christopher J CJ Pontious Corbin C Kovalenko Ilya I Lapienyte Laura L Dreyer Stephan S Lee Ho-Joon HJ Thurston Galloway G Zhang Yaqing Y Lazarus Jenny J Sajjakulnukit Peter P Hong Hanna S HS Kremer Daniel M DM Nelson Barbara S BS Kemp Samantha S Zhang Li L Chang David D Biankin Andrew A Shi Jiaqi J Frankel Timothy L TL Crawford Howard C HC Morton Jennifer P JP Pasca di Magliano Marina M Lyssiotis Costas A CA

Cell metabolism 20190228 6

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 o ...[more]

PMID: 30827862

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Project description:BackgroundPancreatic cancer retains a poor prognosis among the gastrointestinal cancers. It affects 230,000 individuals worldwide, has a very high mortality rate, and remains one of the most challenging malignancies to treat successfully. Treatment with gemcitabine, the most widely used chemotherapeutic against pancreatic cancer, is not curative and resistance may occur. Combinations of gemcitabine with other chemotherapeutic drugs or biological agents have resulted in limited improvement.MethodsIn order to improve gemcitabine response in pancreatic cancer cells, we utilized a synthetic lethal RNAi screen targeting 572 known kinases to identify genes that when silenced would sensitize pancreatic cancer cells to gemcitabine.ResultsResults from the RNAi screens identified several genes that, when silenced, potentiated the growth inhibitory effects of gemcitabine in pancreatic cancer cells. The greatest potentiation was shown by siRNA targeting checkpoint kinase 1 (CHK1). Validation of the screening results was performed in MIA PaCa-2 and BxPC3 pancreatic cancer cells by examining the dose response of gemcitabine treatment in the presence of either CHK1 or CHK2 siRNA. These results showed a three to ten-fold decrease in the EC50 for CHK1 siRNA-treated cells versus control siRNA-treated cells while treatment with CHK2 siRNA resulted in no change compared to controls. CHK1 was further targeted with specific small molecule inhibitors SB 218078 and PD 407824 in combination with gemcitabine. Results showed that treatment of MIA PaCa-2 cells with either of the CHK1 inhibitors SB 218078 or PD 407824 led to sensitization of the pancreatic cancer cells to gemcitabine.ConclusionThese findings demonstrate the effectiveness of synthetic lethal RNAi screening as a tool for identifying sensitizing targets to chemotherapeutic agents. These results also indicate that CHK1 could serve as a putative therapeutic target for sensitizing pancreatic cancer cells to gemcitabine.

Dataset Information

Macrophage-Released Pyrimidines Inhibit Gemcitabine Therapy in Pancreatic Cancer.

Publications

Macrophage-Released Pyrimidines Inhibit Gemcitabine Therapy in Pancreatic Cancer.

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