Obesity is a known risk factor for the development of pancreatic cancer, one of the deadliest types of malignancies. In recent years it has become clear that the pancreatic microenvironment is critically involved and a contributing factor in accelerating pancreatic neoplasia. In this context obesity-associated chronic inflammation plays an important role. Among several immune cells, macrophages have been shown to contribute to obesity-induced tissue inflammation. This review article summarizes the current knowledge about the role of pancreatic macrophages in early pancreatic cancer development. It describes the heterogenous origin and mixture of pancreatic macrophages, their role in pancreatic endocrine and exocrine pathology, and the impact of obesity on islet and stromal macrophages. A model is postulated, by which during obesity monocytes are recruited into the pancreas, where they are polarized into pro-inflammatory macrophages that drive early pancreatic neoplasia. This occurs in the presence of local inflammatory, metabolic, and endocrine signals. A stronger appreciation and more detailed knowledge about the role of macrophages in early pancreatic cancer development will lead to innovative preventive or interceptive strategies.

Pancreatic ductal adenocarcinoma (PDAC) remains an aggressive disease that is expected to become the second cause of cancer fatalities during the next decade. As therapeutic options are limited, novel targets, and agents for therapeutic intervention are urgently needed. Previously, we identified potent positive crosstalk between insulin/IGF-1 receptors and G protein-coupled (GPCR) signaling systems leading to mitogenic signaling in PDAC cells. Here, we show that a combination of insulin and the GPCR agonist neurotensin induced rapid activation of Src family of tyrosine kinases (SFK) within PANC-1 cells, as shown by FAK phosphorylation at Tyr576/577 and Tyr861, sensitive biomarkers of SFK activity within intact cells and Src416 autophosphorylation. Crucially, SFKs promoted YAP nuclear localization and phosphorylation at Tyr357, as shown by using the SFK inhibitors dasatinib, saracatinib, the preferential YES1 inhibitor CH6953755, siRNA-mediated knockdown of YES1, and transfection of epitogue-tagged YAP mutants in PANC-1 and Mia PaCa-2 cancer cells, models of the aggressive squamous subtype of PDAC. Surprisingly, our results also demonstrate that exposure to SFK inhibitors, including dasatinib or knockdown of YES and Src induces ERK overactivation in PDAC cells. Dasatinib-induced ERK activation was completely abolished by exposure to the FDA-approved MEK inhibitor trametinib. A combination of dasatinib and trametinib potently and synergistically inhibited colony formation by PDAC cells and suppressed the growth of Mia PaCa-2 cells xenografted into the flank of nude mice. The results provide rationale for considering a combination(s) of FDA-approved SFK (dasatinib) and MEK (e.g., trametinib) inhibitors in prospective clinical trials for the treatment of PDAC.

Pancreatic ductal adenocarcinoma (PDAC), a highly lethal disease with limited therapeutic options, may benefit from repurposing of FDA-approved drugs in preventive or interceptive strategies in high-risk populations. Previous animal studies demonstrated that the use of metformin and statins as single agents at relatively high doses restrained PDAC development. Here, four-week-old mice expressing KrasG12D in all pancreatic lineages (KC mice) and fed an obesogenic high fat, high calorie diet that promotes early PDAC development were randomized onto low dosage metformin, simvastatin, or both drugs in combination administered orally. Dual treatment attenuated weight gain, fibro-inflammation, and development of advanced PDAC precursor lesions (pancreatic intraepithelial neoplasia [PanIN]-3) in male KC mice, without significant effect in females or when administered individually. Dual-treated KC mice had reduced proliferation of PanIN cells and decreased transcriptional activity of the Hippo effectors, YAP and TAZ, which are important regulators of PDAC development. Metformin and simvastatin also synergistically inhibited colony formation of pancreatic cancer cells in vitro. Together, our data demonstrated that a combination of low doses of metformin and simvastatin inhibits PDAC development and imply that both drugs are promising agents for being tested in clinical trials for preventing pancreatic cancer progression.