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Oncoimmunology. 2016 Jun 21;5(8):e1191731. doi: 10.1080/2162402X.2016.1191731. eCollection 2016 Aug.

Warburg metabolism in tumor-conditioned macrophages promotes metastasis in human pancreatic ductal adenocarcinoma.

Author information

1
Singapore Immunology Network (SIgN), Biomedical Sciences Institute, ASTAR , Immunos, Singapore.
2
BioSystems and Micromechanics IRG, Singapore-MIT Alliance for Research and Technology (SMART) , Singapore.
3
Raffles Institution , Singapore.
4
Bioprocessing Technology Institute, ASTAR , Centros, Singapore.
5
NCCS-VARI Translational Research Laboratory, National Cancer Center , Singapore.
6
Centre for Translational Medicine NUS Yong Loo Lin School of Medicine, CSI Singapore , Singapore.
7
BioSystems and Micromechanics IRG, Singapore-MIT Alliance for Research and Technology (SMART), Singapore; Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA.

Abstract

Patients with pancreatic ductal adenocarcinoma (PDAC) face a clinically intractable disease with poor survival rates, attributed to exceptionally high levels of metastasis. Epithelial-to-mesenchymal transition (EMT) is pronounced at inflammatory foci within the tumor; however, the immunological mechanisms promoting tumor dissemination remain unclear. It is well established that tumors exhibit the Warburg effect, a preferential use of glycolysis for energy production, even in the presence of oxygen, to support rapid growth. We hypothesized that the metabolic pathways utilized by tumor-infiltrating macrophages are altered in PDAC, conferring a pro-metastatic phenotype. We generated tumor-conditioned macrophages in vitro, in which human peripheral blood monocytes were cultured with conditioned media generated from normal pancreatic or PDAC cell lines to obtain steady-state and tumor-associated macrophages (TAMs), respectively. Compared with steady-state macrophages, TAMs promoted vascular network formation, augmented extravasation of tumor cells out of blood vessels, and induced higher levels of EMT. TAMs exhibited a pronounced glycolytic signature in a metabolic flux assay, corresponding with elevated glycolytic gene transcript levels. Inhibiting glycolysis in TAMs with a competitive inhibitor to Hexokinase II (HK2), 2-deoxyglucose (2DG), was sufficient to disrupt this pro-metastatic phenotype, reversing the observed increases in TAM-supported angiogenesis, extravasation, and EMT. Our results indicate a key role for metabolic reprogramming of tumor-infiltrating macrophages in PDAC metastasis, and highlight the therapeutic potential of using pharmacologics to modulate these metabolic pathways.

KEYWORDS:

Metabolism; macrophages; metastasis; pancreatic cancer

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