Scientists have discovered an essential mechanism in the spread of cancer. A team led by professor Massimiliano Mazzone (VIB-KU Leuven) and professor Alessandra Castegna (University of Bari) has demonstrated a way to alter the metabolism of macrophages, a particular type of white blood cell often responsible for supporting tumor growth. They found that reducing the glutamine levels of these macrophages changes their behavior: instead of supporting cancer, the macrophages change back into ‘good’ cells and fight the disease. These groundbreaking findings potentially offer new strategies for immunotherapy. The conclusions of the study are published in the leading scientific journal Cell Reports.
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Macrophages play a crucial role in our immune systems: these white blood cells attack foreign micro-organisms and remove harmful substances from the body. In doing so, they also infiltrate tumors and fight cancer cells, aiming to stop the progression of the disease. However, some cancer cells survive this initial attack. Those survivors then turn their enemies – the macrophages – into their allies and program them to support tumor growth.
Glutamine synthetase drives metastasis
While the properties of macrophages have already been extensively studied, this alteration of the cells’ metabolism remained puzzling. These research avenues are being explored by Rosa Martín-Pérez, Erika Palmieri and Alessio Menga in the teams of Mazzone (VIB-KU Leuven Center for Cancer Biology) and Castegna (University of Bari).
The study focused on the role of glutamine synthetase (GS), an enzyme crucial to the creation of proteins. The results show that GS is essential to sustaining ‘pro-tumoral’ macrophages. Consequently, the study suggests that blocking GS in those macrophages stimulates glycolysis (the process by which they convert sugar into energy), which in turn normalizes the tumor’s blood vessel growth and reduces metastasis.
Mazzone: “Both in vitro and in vivo, we were surprised to see how changing the metabolism of the macrophages impacted tumor growth. Inhibiting glutamine synthetase led the hijacked cells to return to their original purpose: fighting cancer cells as an essential element of the immune system. What’s more, our results point to the inhibition of GS as a key therapeutic way to skew macrophages towards preventing metastases. This could be done pharmacologically or by genetically targeting GS.”
Developing novel drugs that hinder tumor growth
The results of the pioneering study stress the importance of metabolic immunotherapy strategies in the fight against cancer.
Mazzone: “Our research proves that both the expression and the activity of glutamine synthetase are markers of malignant macrophages in tumors, and that blocking GS alters the cells’ metabolism in a way that may help hinder cancer growth. This generates exciting possibilities for the development of specific drugs. The VIB Discovery Sciences team has already established a screening assay to identify GS inhibitors which can serve as a starting point towards development of specific and potent GS drugs.”
Pharmacologic or genetic targeting of glutamine synthetase skews macrophages towards an M1-like phenotype and inhibits tumor metastasis, M. Palmieri et al., Cell Reports 2017