MYC-driven Core Regulatory Circuits in Neuroblastoma
Neuroblastoma is a tumor of the developing nervous system that occurs in very young children with a median age of 17 months. While neuroblastoma is the diagnosis for just 10% of pediatric cancer patients, it accounts for more than 15% of childhood cancer deaths as many high-risk tumors never achieve a durable response to current therapies. My research efforts are focused on understanding the function of MYC family oncogenes in neuroblastoma tumorigenesis, as well as the genes they synergize with to promote malignancy. Recent advances have fundamentally changed our understanding of how cell identity and disease states are maintained. We have recently discovered that MYC works in concert with a small group of core transcription factors responsible for directing the entire cellular gene expression program. These master regulators bind cooperatively to noncoding regulatory elements known as super-enhancers, which are essential in driving expression of the genes required for cellular identity and in the case of diseases such as cancer, malignancy.
Using a combination of innovative computational and molecular approaches, I am now dissecting the mechanisms of this core transcriptional unit and determining their specific roles in the establishment and maintenance of tumor cell states. Additionally, I am elucidating the mechanism of action for clinically-used therapeutics targeting transcription to determine how they epigenetically reprogram neuroblastoma cell identity. Ultimately, this research could lead to the development of next-generation circuitry-directed therapeutics targeting the essential factors required for neuroblastoma cell growth and survival.