Targeting Glycolysis in Macrophages Confers Protection Against Pancreatic Ductal Adenocarcinoma.
Hweixian Leong PennyJe Lin SieowSin Yee GunMai Chan LauBernett LeeJasmine TanCindy PhuaFlorida TohYvonne NgaWei Hseun YeapBaptiste JanelaDilip KumarHao ChenJoe Poh Sheng YeongJustin A KenkelAngela PangDiana LimHan Chong TohTony Lim Kiat HonChristopher I JohnsonHanif Javanmard KhamenehAlessandra MortellaroEdgar G EnglemanOlaf RotzschkeFlorent GinhouxJean-Pierre AbastadoJinmiao ChenSiew Cheng WongPublished in: International journal of molecular sciences (2021)
Inflammation in the tumor microenvironment has been shown to promote disease progression in pancreatic ductal adenocarcinoma (PDAC); however, the role of macrophage metabolism in promoting inflammation is unclear. Using an orthotopic mouse model of PDAC, we demonstrate that macrophages from tumor-bearing mice exhibit elevated glycolysis. Macrophage-specific deletion of Glucose Transporter 1 (GLUT1) significantly reduced tumor burden, which was accompanied by increased Natural Killer and CD8+ T cell activity and suppression of the NLRP3-IL1β inflammasome axis. Administration of mice with a GLUT1-specific inhibitor reduced tumor burden, comparable with gemcitabine, the current standard-of-care. In addition, we observe that intra-tumoral macrophages from human PDAC patients exhibit a pronounced glycolytic signature, which reliably predicts poor survival. Our data support a key role for macrophage metabolism in tumor immunity, which could be exploited to improve patient outcomes.
Keyphrases
- mouse model
- oxidative stress
- adipose tissue
- end stage renal disease
- healthcare
- endothelial cells
- chronic kidney disease
- palliative care
- type diabetes
- squamous cell carcinoma
- metabolic syndrome
- high fat diet induced
- radiation therapy
- quality improvement
- artificial intelligence
- insulin resistance
- peritoneal dialysis
- wild type
- patient reported