U of T Researchers Explore How Glioblastoma Development Mirrors Injury Responses

The Link Between Gliomagenesis and Brain Injury Responses

Glioblastoma is one of the most highly aggressive and deadly brain cancers: not only does it grow quickly, but it resists treatment and spreads into nearby brain tissue, making it hard to cure. Despite progress in cancer research, glioblastoma is nearly always fatal. Most patients survive about 15 months after diagnosis.

Scientists traditionally studied this disease by examining tumours removed during surgery when they were large and the patients suffering from severe symptoms. However, this method misses crucial information about how tumours begin and develop in their early, symptom-free stages.

Innovative Research Methods for Studying Gliomagenesis

Researchers at the University of Toronto's Department of Molecular Genetics have sought to address this gap. They used innovative methods to study gliomagenesis, or tumour formation, at its earliest stages.

The research team, led by Dr. Akram Hamed and Dr. Peter Dirks, a professor of the Department of Molecular Genetics, used genetically engineered mice and advanced MRI to start and monitor tumour formation from its inception.

By collecting samples at multiple stages of tumour growth, the team was able to map the entire process. They used single-cell sequencing, a cutting-edge technology that allows for detailed analysis of individual cells within the tumour.

"Our work provides a detailed map of the entire process of tumour development and reveals new insights that could lead to better treatment strategies," said Hamed. 

The study was published recently in Nature.

Discovery of a New Stem Cell–Like Compartment

This research found a new stem cell-like compartment in early glioblastoma, which appears to play a crucial role in driving the disease's initiation and progression. Notably, the researchers discovered a malignant cell state that strongly resembles neural crest cells, a type of stem cell typically found during early embryonic development but not in the adult brain under normal conditions.

Hamed adds, "We found that these neural crest-like cells are highly abundant in the early stages of tumour growth, but not in the late stage," Hamed explained. "Our results suggest that these cells have a critical role in supporting tumour growth and the cellular diversity observed in these tumours."

The Tumour’s Mimicry of an Injury Response

The study also found that glioblastoma development triggers a response similar to a brain injury. Following the induction of genetic changes in brain stem cells, the researchers discovered the activation of an environment that resembles the body's natural healing process.

"Our experiments suggest that glioblastoma might arise, in part, because the brain is trying to heal itself," explains Dr. Dirks. "When genetically vulnerable cells are exposed to an injury-like environment, it triggers a response that can lead to tumour formation. This opens up the possibility that glioblastoma could be intercepted by targeting these injury-like processes."

Dr. Hamed also highlights the significance of this finding: "Understanding this injury-like response gives us a new way to think about early detection and treatment. If we can identify these injury signals early, we might be able to intervene before the tumour fully develops." 

This finding suggests that glioblastoma may partially arise following the brain's misguided activation of an injury response. The activation of neural crest-like cells during this injury response could be a key driver of early tumour growth.

What's next?

This research from the University of Toronto's Department of Molecular Genetics significantly advances our understanding of glioblastoma. By revealing the presence of neural crest-like cells and an injury-like response during the early stages of tumour formation, the study opens new possibilities for early intervention and treatment.

By targeting the newly found malignant cell types and injury-like processes that are activated in early tumour development, we may intercept glioblastoma before it becomes incurable. This could represent a significant shift in the approach to treating brain tumours, moving from reactive surgery to proactive intervention, offering hope for improved outcomes.