In brief

Disabling GLUT1 in tumour-associated macrophages cuts off energy supplied to tumours and triggers a strong immune response against them.

© A*STAR Research

Glucose-guzzling immune cells aggravate tumours

25 Oct 2022

Researchers discover that the deletion of a gene linked to glucose metabolism leads to smaller pancreatic tumours and better patient survival.

Much like comparing an old, diesel-powered car with today’s electric vehicles, cancer cells run on very different energy systems than healthy cells. Almost all tumours generate energy from glucose through a metabolic process called glycolysis, which is much faster than the metabolic pathways used by healthy tissues.

While scientists have known about tumours’ dependence on glycolysis since the 1930s, much less is known about the metabolisms of other cells within the tumour microenvironment. A prime example is a macrophage, an immune cell thought to promote inflammation and tumour growth.

Advances in understanding the metabolic pathways utilised by these immune cells could unlock new therapeutic targets to stop tumours, said Siew Cheng Wong, Director of Research Administration at A*STAR’s Singapore Immunology Network (SIgN). In their study, Wong and a team of cancer experts explored links between the metabolism of macrophages in pancreatic tumours and cancer patient survival.

Using metabolic assays, Wong and her team found that much like cancer cells, tumour-associated macrophages (TAMs) were heavily reliant on glycolysis for their metabolic needs. Next, they studied how TAM glycolysis influenced disease outcomes of an orthotopic pancreatic cancer mouse model that lacked functional GLUT1, a glycolysis gene involved in ferrying glucose into cells on macrophages through genetic alteration.

In an unexpected result, they found that mice lacking GLUT1 on macrophages had significantly smaller tumours and survived longer. “The fact that GLUT1 deletion appeared to shut down glycolysis completely in macrophages was very surprising to us,” said Wong, explaining that the team anticipated that the many other related glucose transporters would have compensated for the missing GLUT1.

Deactivating GLUT1 and thereby preventing glycolysis in macrophages also triggered an influx of cancer-killing immune cells such as cytotoxic T lymphocytes into the tumours in mice.

Interestingly, a similar phenomenon is likely to be happening in humans too. The team searched clinical databases of pancreatic cancer and found that patients with lower levels of GLUT1 expression had better survival outcomes. This means that GLUT1, alongside other metabolic biomarkers, could one day serve as a sort of signature to help predict survival outcomes in pancreatic cancer patients.

“More often than not, preclinical observations are not recapitulated in the clinic,” Wong said. “We were very pleasantly surprised to observe such fidelity and translatability between our mouse data and patient outcomes.”

Still, Wong explains that given the complexity of macrophage biology, future studies need to dig deeper into the intricacies of glycolysis and tumour progression before GLUT1 can be regarded as a potential treatment target.

The A*STAR-affiliated researchers contributing to this research are from the Singapore Immunology Network (SIgN) and A*STAR Skin Research Labs (A*SRL).

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Penny, H.L., Sieow, J.L., Gun, S.Y., Lau, M.C., Lee, B. et al. Targeting Glycolysis in Macrophages Confers Protection Against Pancreatic Ductal Adenocarcinoma, International Journal of Molecular Sciences 22:6350 (2021) | article

About the Researchers

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Siew Cheng Wong

Director of Research Administration

Singapore Immunology Network (SIgN)
Siew Cheng Wong was awarded the Glaxo-EDB scholarship to pursue her PhD studies in Molecular Biology at University College London. She returned to Singapore in 2000 to join Kong Peng Lam’s lab at the Institute of Molecular and Cell Biology (IMCB) where she started her postdoctoral journey in immunology research. She continued her immunology research with Philippe Kourilsky in 2006 at the Singapore Immunology Network (SIgN). In 2012, she became a Principal Investigator and continued her research in myeloid cell biology. She left research work in 2018 and is currently the Director of Research Administration at SIgN.
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Xianne Leong Penny

Xianne Penny was part of the initial A*STAR NSS-PhD cohort when the programme began. She graduated summa cum laude in immunology from Brown University and completed doctoral work in immunology under the guidance of Ed Engleman at Stanford University’s School of Medicine. Upon return to Singapore, she performed 5 ½ years of postdoctoral work at the Singapore Immunology Network (SIgN), first under the supervision of Jean-Pierre Abastado and then completing her scholarship commitment under Siew Cheng Wong. She has since made the leap to industry, providing immunogenicity monitoring support to Amgen’s immuno-oncology assets from its headquarters in Thousand Oaks, California.

This article was made for A*STAR Research by Wildtype Media Group