Scientists identify key molecular process driving deadly childhood brain cancer

An international group of scientists has identified a key molecular process that drives a deadly form of childhood brain cancer, potentially offering a much-needed, new therapeutic target.

Published in leading international journal Molecular Cell, the new study has revealed how a rare but devastating childhood brain cancer-called Diffuse Midline Glioma (DMG)-hijacks the cell's gene control machinery to fuel its growth. The findings could point the way to urgently needed new treatments for this currently incurable disease.

DMG is a tumor that develops deep in the brain and primarily affects children and young adults. Nearly all cases carry a key genetic change: a mutation in a protein called histone H3, which helps package DNA inside cells. This mutation disrupts a crucial chemical mark-known as H3K27me3-that normally acts like a stop sign to silence genes. 

Scientists had long believed this disruption caused genes to turn on when they shouldn't. But in a surprising twist, the researchers behind the new study found that parts of this "stop sign" system still remain-and the tumor actually depends on them to survive. 

Using cutting-edge genetic screens and molecular tools, the team discovered that a very specific gene-silencing complex-called CBX4/PCGF4-cPRC1-is essential for the tumor's growth. Although it makes up less than 5% of the related silencing machinery in the cancer cells, this particular complex plays an outsized role in shutting down genes that would otherwise prevent the tumor from growing. 

The study also revealed how a previously unknown region in the CBX4 protein helps it form a special partnership with PCGF4, enabling this harmful gene repression. 

"Although this form of PRC1 gene-silencing complex represents less than 5% of PRC1 in these tumors, our research shows it is essential for tumor growth," said Professor Adrian Bracken, co-lead investigator on the study from Trinity College Dublin's Smurfit Institute of Genetics. 

"By specifically targeting this rare form of PRC1, it may be possible to develop more precise treatments that minimise side effects that can arise with broader-acting therapies."

This discovery sheds light on a key mechanism driving DMG and identifies CBX4 as a promising drug target. Our findings suggest that interfering with CBX4's interaction with chromatin or its partner protein PCGF4 could disrupt the tumor's gene-silencing machinery - potentially paving the way for new treatment strategies against this devastating disease."

Dr. Gerard Brien, co-lead investigator from the University of Edinburgh

This work was led by two outstanding former PhD researchers from the Bracken Lab, Dr Eimear Lagan and Dr Daire Gannon, who collaborated closely throughout their doctoral studies to address this challenging disease. Dr Lagan completed her PhD under the joint supervision of Dr Bracken and Dr Gerry Brien, conducting her final research in Dr. Brien's lab at the University of Edinburgh.

Claire Kilty, Head of Research at the Irish Cancer Society, said: "The findings in this important piece of research have identified new targets for treatment for a rare and incurable form of childhood brain cancer. The Irish Cancer Society is proud to have provided funding for this research, which could potentially lead to a new treatment pathway for a currently incurable cancer.

"Cancer research in Ireland has a huge impact on the lives of people affected by cancer. It is a driving force in improving treatments and outcomes, and quality of life after cancer. We are proud to be the largest voluntary funder of cancer research in the State, which is made possible through the generosity of the public. We envision a future where everyone survives cancer, and funding groundbreaking cancer research like this brings us closer to that goal."