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 i

SUBMITTER: Halbrook CJ 

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

REPOSITORIES: biostudies-literature