Warburg metabolism in tumor-conditioned macrophages promotes metastasis in human pancreatic ductal adenocarcinoma.
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.
Singapore Immunology Network (SIgN), Biomedical Sciences Institute, ASTAR , Immunos, Singapore.
Hweixian Leong
HL
Penny
Singapore Immunology Network (SIgN), Biomedical Sciences Institute, ASTAR , Immunos, Singapore.
Je Lin
JL
Sieow
BioSystems and Micromechanics IRG, Singapore-MIT Alliance for Research and Technology (SMART) , Singapore.
Giulia
G
Adriani
Singapore Immunology Network (SIgN), Biomedical Sciences Institute, ASTAR , Immunos, Singapore.
Wei Hseun
WH
Yeap
Singapore Immunology Network (SIgN), Biomedical Sciences Institute, ASTAR , Immunos, Singapore.
Peter
P
See Chi Ee
Singapore Immunology Network (SIgN), Biomedical Sciences Institute, ASTAR , Immunos, Singapore.
Boris
B
San Luis
Singapore Immunology Network (SIgN), Biomedical Sciences Institute, ASTAR , Immunos, Singapore.
Bernett
B
Lee
Raffles Institution , Singapore.
Terence
T
Lee
Bioprocessing Technology Institute, ASTAR , Centros, Singapore.
Shi Ya
SY
Mak
Bioprocessing Technology Institute, ASTAR , Centros, Singapore.
Ying Swan
YS
Ho
Bioprocessing Technology Institute, ASTAR , Centros, Singapore.
Kong Peng
KP
Lam
NCCS-VARI Translational Research Laboratory, National Cancer Center , Singapore.
Choon Kiat
CK
Ong
Centre for Translational Medicine NUS Yong Loo Lin School of Medicine, CSI Singapore , Singapore.
Ruby Y J
RY
Huang
Singapore Immunology Network (SIgN), Biomedical Sciences Institute, ASTAR , Immunos, Singapore.
Florent
F
Ginhoux
Singapore Immunology Network (SIgN), Biomedical Sciences Institute, ASTAR , Immunos, Singapore.
Olaf
O
Rotzschke
BioSystems and Micromechanics IRG, Singapore-MIT Alliance for Research and Technology (SMART), Singapore; Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA.
Roger D
RD
Kamm
Singapore Immunology Network (SIgN), Biomedical Sciences Institute, ASTAR , Immunos, Singapore.
Siew Cheng
SC
Wong
Metabolism; macrophages; metastasis; pancreatic cancer