MSc by Research Regenerative Medicine and Tissue Repair

Mapping the origins of childhood brain cancer

CRM scientists have made a breakthrough in understanding how aggressive brain tumours develop in children and why they occur in specific regions of the brain.

The research has found that the specific brain region of the originating cell that gives rise to the tumour has a profound impact on tumour formation. Mapping the cancer’s origins helps shed light on the different types of childhood glioblastoma and identifies new vulnerabilities that may be explored in the future search for treatments.

Glioblastoma is the most aggressive form of brain cancer. While rare in children, making up just 8% of childhood brain and spinal cord tumours in the UK, it can be particularly devastating, as their location makes them hard to treat. Just a quarter of glioblastoma patients survive more than one year.

Tumours can arise in different parts of the brain and can appear very similar, however they have discreet mutations depending on their location. This has so far been a puzzle for scientists, who have been unable to explain why different mutations and cancers arise in different regions of the brain.

The study, led by Professor Steven Pollard, set out to understand the origins of these aggressive childhood brain tumours and why certain mutations give rise to different forms of the disease. Working in the laboratory culture dish they were able to test the responses of normal brain stem cells obtained from forebrain or hindbrain to different mutations and see how they responded. It gave Professor Pollard and his team the opportunity to explore the very earliest stages of brain tumour formation, which is otherwise impossible using patient derived tumour cells.

They found that the location of the cells – their regional identity – impacts how they will respond to different mutations. A powerful mutation can be dangerous in one region of the brain, however, similar cells from another region of the brain can detect that it is dangerous and have a ‘safety switch’ stopping any further development. For example, a mutation that arises in the forebrain can cause tumours in the region, while the same mutation will not have the same impact on cells from the hindbrain.

These results can help scientists understand why different mutations and cancers arise in different anatomical regions of the brain, with varying degrees of aggressiveness and help us understand the origins of childhood brain cancer and how different tumours work. Ultimately, this new insight may help future development of more effective treatments for the disease.

For a long time, how these childhood forms of glioblastoma develop has been a bit of a puzzle. We have been unsure as to why certain gene mutations appear in certain regions and with different levels of aggressiveness. Our research answers this question and has revealed the importance of particular class of protein termed transcription factors, which control the cell identity and have such a dramatic impact on how these mutations operate. Our work adds to the growing evidence that paediatric cancer cells have become ‘stuck’ in their immature stem cell-like state. We are also excited by the possibilities the new cellular models we have built can be used in development and testing of new treatments.

Professor Steven Pollard, Group Leader, Centre for Regenerative Medicine

The study has been published in the scientific journal Cell Stem Cell and was funded by Children with Cancer UK – the UK’s leading charity dedicated to research into childhood cancer.

This Children with Cancer UK funded research project has employed state of the art technology to advance our knowledge of how and why brain tumours develop in different areas of the growing brain. We now hope that Professor Pollard’s findings will be harnessed to develop new cancer specific treatments that will be both more effective and cause fewer side effects. This is another excellent example of how charitably funded research can directly impact on survival and quality of survival for patients.

Dr Nick Goulden, Children with Cancer UK

Bressan et al. Regional identity of human neural stem cells determines oncogenic responses to histone H3.3 mutants. Cell Stem Cell 2021.

Steve Pollard Research Group