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2016 ; 5
(8
): e1191731
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Warburg metabolism in tumor-conditioned macrophages promotes metastasis in human
pancreatic ductal adenocarcinoma
#MMPMID27622062
Penny HL
; Sieow JL
; Adriani G
; Yeap WH
; See Chi Ee P
; San Luis B
; Lee B
; Lee T
; Mak SY
; Ho YS
; Lam KP
; Ong CK
; Huang RY
; Ginhoux F
; Rotzschke O
; Kamm RD
; Wong SC
Oncoimmunology
2016[Aug]; 5
(8
): e1191731
PMID27622062
show ga
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.