Nadia Dahmane, PhD, associate professor of developmental biology in neurological surgery and a key investigator at the Weill Cornell Medicine Children’s Brain Tumor Project, has been awarded a pilot NIH grant for deciphering the three-dimensional (3D) genome of pediatric brain tumors. In collaboration with Dr. Katherine Pollard of the Gladstone Institute and Dr. Adam Resnick of the Children’s Hospital of Philadelphia, Dr. Dahmane will be investigating how the disruption of mechanisms controlling normal development, including those controlling acquisition of cell identity, play a role in the development of pediatric brain tumors.
Despite identification of genetic and epigenetic events underlying their biology, pediatric brain tumors remain the most frequent and most fatal of all tumors in children. These tumors arise in developing brain, so Dr. Dahmane’s approach to discovering new therapeutical targets is to study them within the context of their developmental origin.
The grant, nearly $400,000, will allow Dr. Dahmane and her collaborators to explore whether disruption of 3D genome folding during embryonic or postnatal development leads to altered gene expression that causes abnormal cell differentiation and tumorigenesis in the developing brain. The project will begin with determining the 3D genome architecture of atypical teratoid/rhabdoid tumors (AT/RT) and then expand into other malignant brain tumors such as medulloblastoma, ependymoma, and high-grade glioma.
The study leverages a deep-learning model called Akita, developed by Dr. Pollard’s group, that predicts 3D chromatin interaction frequencies from genome sequence alone. It also uses pediatric brain whole-genome sequences from Gabriella Miller Kids First, plus chromatin capture, epigenetic, and expression data from other NIH Common Fund resources such as 4D Nucleome and Genotype-Tissue Expression (GTEx) programs. It is expected that this project will lead to novel research hypotheses and accelerate the discovery of additional regulators of cancer tumorigenesis, and thus to potential therapeutic strategies for these devastating diseases.