Mattias Belting and Anna Bång Rudenstam.
Photo Credit: Tove Smeds
Scientific Frontline: "At a Glance" Summary
- Main Discovery: Aggressive brain tumors, specifically glioblastoma and central nervous system metastases, construct a protective surface layer rich in chondroitin sulfate to shield themselves from toxic lipids and prevent ferroptosis (a form of cell death caused by lipid oxidation).
- Methodology: Researchers analyzed tumor cells isolated directly from patient surgeries and utilized 3D organoid models to replicate the tumor environment; they then experimentally disrupted the formation of the sugar shield while simultaneously blocking the cells' ability to store lipids in droplets.
- Key Data: The study identified two cooperative defense mechanisms: the external chondroitin sulfate sugar shield (acting as a filter) and internal lipid droplets (acting as storage buffers); simultaneously disabling both defenses caused rapid tumor cell collapse and death via ferroptosis.
- Significance: This finding reveals a previously unrecognized metabolic survival strategy that allows cancer cells to adapt to the brain's hostile environment (characterized by oxidative stress and low pH), fundamentally changing the understanding of brain tumor resilience.
- Future Application: The discovery points toward a novel therapeutic strategy that combines agents to strip the sugar shield with inhibitors of lipid storage, potentially sensitizing aggressive tumors to ferroptosis-inducing treatments.
- Branch of Science: Oncology and Cell Biology
- Additional Detail: The same protective sugar shield mechanism was observed in brain metastases originating from malignant melanoma, lung cancer, and kidney cancer, suggesting a common adaptive trait for tumors invading the central nervous system.
For the first time, researchers have identified a previously unrecognized metabolic defense mechanism in aggressive brain tumors: a sugar-rich shield that surrounds tumor cells and protects them against a particularly destructive form of cell death.
Aggressive brain tumors grow in an extreme environment characterized by oxygen and nutrient deficiencies, low pH, and chronic cellular stress. Inside the tumor, conditions would normally damage or kill healthy cells, yet tumor cells adapt in ways that make them highly resilient. At the same time, these tumors are often resistant to currently available treatments.
In a study led from Lund University, published in Nature Cell Biology, researchers now show that tumor cells in aggressive brain tumors - 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 tumors adapt to survive in the extreme tumor 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.
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
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 tumor'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 tumor 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 tumor cells from toxic lipids.
A double layer of metabolic protection against cell death
Tumor 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 prevents them from damaging the cell.
“We found that these two defense mechanisms – the sugar shield and the lipid droplets – cooperate. That led us to ask what would happen if you eliminated 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 tumor cell’s protective sugar shield – while simultaneously blocking the cell’s ability to store lipids in lipid droplets.
When both defense systems were simultaneously disrupted, the tumor cells collapsed. The lipid particles could neither be kept out nor stored, which led to rapid cell death by ferroptosis.
“The experimental combination treatment attacks the tumor cells’ defense mechanisms. When they disappear, the tumor cells become highly vulnerable to oxidized lipids and ferroptosis,” says Anna Bång-Rudenstam.
The results are based on analysis of tumor material from patients, including cells isolated immediately after brain surgery, as well as organoids – three-dimensional tumor models that more closely reflect tumor behavior 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.
Published in journal: Nature Cell Biology
Title: Tumour acidosis remodels the glycocalyx to control lipid scavenging and ferroptosis
Authors: Anna Bång-Rudenstam, Myriam Cerezo-Magaña, Marton Horvath, Hugo Talbot, Emma Gustafsson, Stevanus Jonathan, Chaitali Chakraborty, Itzel Nissen, Kelin Gonçalves de Oliveira, Axel Boukredine, Sarah Beyer, Julio Enriquez Perez, Maria C. Johansson, Lena Kjellén, Emil Tykesson, Anders Malmström, Toin H. van Kuppevelt, Karin Forsberg-Nilsson, Jeffrey D. Esko, Silvia Remeseiro, Johan Bengzon, Valeria Governa, and Mattias Belting
Source/Credit: Lund University | Tove Smeds
Reference Number: ongy021126_01
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