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Experimental model to study the development of brain cancer in children

Researchers from UCL, the German Center for Neurodegenerative Diseases (DZNE) and McGill University, Montreal have published details of a novel laboratory model that replicates the hallmarks of paediatric brain cancer. The research results, published in Cancer Cell, could pave the way for a better understanding of processes driving the development of cancer.

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31 October 2017

Paediatric high-grade glioma is the primary cause of cancer death in children. Genesis of these tumours is believed to be driven by mutations in proteins that disrupt fundamental mechanisms governing the development of the human brain. However, our understanding of these tumours remains incomplete due to the lack of faithful experimental models.

Pediatric high-grade glioma (pHGG) is a devastating illness and the most deadly cancer affecting children. Mutations in "histone 3.3", a DNA-binding protein that acts upon gene expression for regulation of brain function and aging, are considered to play a pivotal role for the development of these tumors. "Current treatment involves surgery, radiation and chemotherapy, albeit with limited success. Most patients die within one to two years from diagnosis," says Professor Paolo Salomoni, senior author of the study, Group Leader of the Nuclear function and metabolism in cancer pathogenesis Research Group at UCL Cancer Institute and Group Leader at DZNE's Bonn site. 

Discovering the underlying mechanisms of brain cancer

"Up to now, there was no truly representative in vivo model to study the underlying mechanisms of this disease," says Professor Salomoni. "That is why we decided to develop a mouse model that recapitulates hallmark pathological features of pHGG. Our findings support the concept that mutations in histone 3.3 alter gene regulation already during embryonic development. This means that the cancer likely starts in utero."

For the study the researchers altered the blueprint of histone 3.3 in mice by genetic engineering. "This model will enable insights into the development of pHGG and provide an opportunity to explore novel therapeutic approaches", Salomoni says. The biologist sees further potential for applications: "Laboratory experiments suggest that alterations in histone 3.3 are implicated not just in brain tumors but also in depression and age-related brain diseases. Our model might therefore help to study DNA associated mechanisms involved in a wide spectrum of diseases."

Targeting paediatric brain cancer

Manav Pathania, first author on the paper adds "This type of childhood brain tumour has a very different genetic makeup compared to tumours in adults. Researchers from around the world have identified certain drugs that seem to work in these children's tumours, but until now there was no way of testing the efficacy of these in a rapid, methodical way. For example, now we can find out whether different mutations present in these tumours impact which drugs work best, or how the immune system responds to these tumours. With this model, these new lines of analysis are opened up, enabling a ramping up of experimental therapy testing and targeting this devastating illness."

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