For the first time, researchers have identified a previously unrecognized metabolic defence mechanism in aggressive brain tumours: a sugar-rich shield that surrounds tumour cells and protects them against a particularly destructive form of cell death.
Aggressive brain tumours grow in an extreme environment characterised by oxygen and nutrient deficiencies, low pH and chronic cellular stress. Inside the tumour, conditions would normally damage or kill healthy cells, yet tumour cells adapt in ways that make them highly resilient. At the same time, these tumours are often resistant to currently available treatments.
In a study led from Lund University, published in Nature Cell Biology, researchers now show that tumour cells in aggressive brain tumours - including glioblastoma and metastases in the central nervous system - can avoid cell death by building up a sugar-rich surface layer around themselves, a mechanism not previously described.
"This changes our understanding of how aggressive brain tumours adapt to survive in the extreme tumour environment in the brain," says Mattias Belting, professor of oncology at Lund University and senior neuro-oncology consultant at Skåne University Hospital, who led the study.
The sugar shield acts as a protective filter that limits the uptake of lipid particles from the surroundings - lipids that could otherwise be toxic in the tumour's internal environment. In this way, cancer cells can avoid ferroptosis, a particularly destructive form of cell death. During ferroptosis, certain lipids undergo oxidation - in simple terms they "turn rancid" - ultimately causing catastrophic cell damage and collapse.
At the molecular level, this sugar shield consists of long sugar chains that accumulate on the tumour cell surface. The researchers show that this structure is particularly rich in a complex sugar structure called chondroitin sulphate, which thickens the sugar shield and protects tumour cells from toxic lipids.
A double layer of metabolic protection against cell death
Tumour cells rely on not one but several survival strategies. In addition to the protective sugar shield, they store lipids in small droplets within the cell. These lipid droplets act as metabolic storage buffers - a sink that captures harmful lipids and prevent them from damaging the cell.
"We found that these two defence mechanisms - the sugar shield and the lipid droplets - cooperate. That led us to ask what would happen if you eliminate both at the same time," says Anna Bång-Rudenstam, doctoral researcher and medical student at Lund University and first author of the study.
The researchers developed experimental strategies to impair the formation of chondroitin sulphate - the key component that builds up the tumour cell's protective sugar shield - while simultaneously blocking the cell's ability to store lipids in lipid droplets.
When both defence systems were simultaneously disrupted, the tumour cells collapsed. The lipid particles could neither be kept out nor stored, which led to rapid cell death by ferroptosis.
"The experimental combination [TS1] [MB2] treatment attacks the tumour cells' defence mechanisms. When they disappear the tumour cells become highly vulnerable to oxidised lipids and ferroptosis," says Anna Bång-Rudenstam.
The results are based on analysis of tumour material from patients, including cells isolated immediately after brain surgery, as well as organoids - three-dimensional tumour models that more closely reflect tumour behaviour in the patient. The researchers also found that the same sugar shield observed in glioblastoma is present in metastases to the central nervous system from malignant melanoma, lung cancer and kidney cancer.
"In the long term, we hope that these findings can help inform the development of more effective treatment strategies for this severely affected patient group," says Mattias Belting.
The study is a collaboration between researchers at Lund University, Umeå University, Uppsala University and the University of California, San Diego and was supported by the Swedish Research Council, the Swedish Cancer Society, the Swedish Childhood Cancer Fund, ALF, Mrs. Berta Kamprad's Cancer Foundation, the Sjöberg Foundation and a donation from Viveca Jeppsson.
