Abstract 1578: Exploring the role of tumor-conditioned macrophage metabolism on extravasation of pancreatic ductal adenocarcinoma cells
Authors: Giulia Adriani, Hweixian L. Penny, Je Lin Sieow, Siew Cheng Wong, Roger D. Kamm
Journal: Cancer Research (2016)

Abstract A persistently low survival rate and more than 80% of patients experiencing relapse after surgery combine to make pancreatic ductal adenocarcinoma (PDAC) the 4th leading cause of death from cancer. Recent studies showed that the presence of tumor-associated macrophages (TAMs) may support cancer cells in each step of the metastatic cascade: growth at the primary site followed by epithelial-mesenchymal transition (EMT), intravasation into lymph and blood vessels, circulation to a distant site, stoppage due to adhesion or size restriction, extravasation into tissue, and colonization in this secondary organ. However, the role of TAMs and their metabolic profile in tumor progression need further investigation. The objective of our studies was to examine the potential for macrophages to switch from oxidative phosphorylation to aerobic glycolysis (the Warburg effect), similar to what is observed in cancer cells, and how this metabolic conversion may influence their pro-metastatic activity. To address this question we differentiated human peripheral blood monocytes with non tumor- and tumor-conditioned media to obtain macrophages and TAMs, respectively. First, we showed in a live glycolytic stress test that TAMs had a greater glycolytic capacity compared to non tumor-conditioned macrophages. Next, a 3D in-vitro microfluidic extravasation assay consisting of an endothelial monolayer was used to assess the effect of macrophages on PDAC cell extravasation across the endothelial wall into an extracellular matrix-like hydrogel. We observed that the extravasation propensity of PDAC cells was increased by the presence of TAMs but was not significantly affected by non tumor-conditioned macrophages. This suggests that the tumor-conditioned media fostered monocyte differentiation toward pro-metastatic macrophages. To assess if the macrophage metabolic switch toward glycolysis was the key factor promoting the increment in cancer cell extravasation, we treated the TAMs with 2-Deoxyglucose (2-DG), a competitive inhibitor of glycolysis at the level of hexokinase. Indeed, we observed a significant reduction in the rate of PDAC cell extravasation when TAMs were treated with 2-DG compared to untreated TAMs. Our results confirmed that the glycolytic metabolism was involved in modulating pro-tumoural macrophage function. Taken together, our data suggest that the macrophage metabolic pathway is a potential therapeutic target for controlling immune cell contributions to tumor progression and that patient responses to current treatments might be improved by inhibition of macrophage glycolysis. Citation Format: Giulia Adriani, Hweixian L. Penny, Je Lin Sieow, Siew Cheng Wong, Roger D. Kamm. Exploring the role of tumor-conditioned macrophage metabolism on extravasation of pancreatic ductal adenocarcinoma cells. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1578.