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).
