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

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.

Leptin in the regulation of the immunometabolism of adipose tissue-macrophages

“…Mϕs produce numerous types of cytokines, which mediate pro‐ or anti‐inflammatory responses upon specific stimuli . Mϕs are very plastic cells and can undergo polarization toward distinct profiles . There is a large variation of Mϕ phenotypes, but for didactic reasons we use a well‐accepted model with the populations that are best described .…”

Cancer metabolism gets physical

“…These challenges might be overcome by complementing PDX models with physiologically relevant in vitro assays that can be used to quickly and accurately perform high-throughput screening with potential therapeutic agents and provide mechanistic information to guide treatment. As researchers develop new methods for maintaining the full complement of immune cells in cultured systems, advanced in vitro models can be used to examine the impact of immune cells and immune targeted therapies on tumor metabolism and the microenvironment as well as their role in tumor clearance, questions that cannot be readily addressed in immunodeficient murine systems (9, 51, 52). …”

Micro‐environment and intracellular metabolism modulation of adipose tissue macrophage polarization in relation to chronic inflammatory diseases

“…115 In this work, peritumoral AT had significantly decreased adipocyte size and had an increased area of fibrosis and infiltration of macrophages, including the M1 and M2 phenotypes, and anterior AT, which was distant from the tumours, had fewer blood vessels and fewer M1 macrophages in a melanoma mouse model, suggesting that M2 rather than M1 macrophages play a major role in the growth of malignant cells by acting as a proximate source. 115 Because metabolic remodelling of tumourassociated macrophages has been shown to affect the development of tumours in humans, 121 targeting metabolic remodelling that mediates tumour-associated ATM polarization should receive more attention.…”