Game Changer Grant Awarded to Chau Lu

Pediatric high-grade gliomas are aggressive brain tumors that are extremely difficult to treat. These tumors often contain a mutation in proteins known as histones. This mutation (H3K27M) disrupts how cells turn genes on and off, and prevents brain cells from maturing properly, leaving them stuck in an immature, fast-growing state - fueling cancer growth. Previous studies have investigated how this mutation changes the linear 2D genome landscape. However, the human genome is organized into a 3D structure that controls the expression of genes, and we still don’t fully understand how H3K27M mutation affects the 3D structure of DNA inside the nucleus.

For this proposal, we aim to understand how childhood glioma carrying H3K27M mutation hijacks 3D DNA
structures to grow. Our preliminary findings suggest that these mutations may cause abnormal DNA folding patterns that resemble those seen in stem cells. Our research will investigate how this mutation creates abnormal DNA loops and clusters that keep anti-cancer genes turned off and prevent normal brain cell maturation. Specifically, we aim to discover:
(1) How does the mutation change the way DNA folds? We will use advanced imaging techniques to visualize these DNA loops and structures in brain tumor cells compared to normal cells.
(2) Does this 3D folding help cancer cells stay aggressive? We will test whether re-creating these
DNA loops in non-cancerous cells makes them behave more like tumor cells.
(3) Can we disrupt these abnormal loops to stop tumor growth? We will genetically modify tumor cells to remove or change a key protein (CBX2) that may be responsible for keeping these cancer-fueling loops in place. Then, we will test whether this change helps brain cells mature normally again or slows tumor progression in mice.

Ultimately, the goal is to identify new treatment strategies for these aggressive cancers by targeting the way
these mutated histones affect DNA organization. If we confirm that these DNA loops are essential for tumor growth, we could develop new drugs to break them apart—potentially offering a more precise and effective treatment for children with these deadly brain tumors.