MYC-driven Core Regulatory Circuits in Neuroblastoma
Background: 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.
Project Goal: 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.
Project Update 2022: About 30 years ago, researchers found that compounds derived from retinoic acid, called retinoids, slowed the growth of neuroblastoma cells in laboratory dishes and caused them to differentiate – to look and act more like normal nerve cells. For decades, scientists have wondered exactly how this process works. The answer, we discovered, is by reprogramming the activity of two crucial pairs of genes with such precision that the drug almost seems to have been expressly designed for that purpose. The findings, reported in Science Advances, solve a longstanding puzzle about retinoic acid’s mode of action in neuroblastoma and reveal why the drug is effective in some patients but not others. Suppose the human genome is thought of as a control room with levers to raise or lower the activity of thousands of genes. In that case, ATRA can adjust at least four of those levers in a way that is particularly harmful to neuroblastoma cells with excess copies of MYCN. We went on to show how ATRA exercises such control over these critical genes. The genome contains regions where multiple enhancers are clustered like beads on a necklace. These regions, known as super-enhancers, deliver an extra jolt of activity to the genes they regulate. We discovered that ATRA alters the way super-enhancers position themselves on a set of genes that include PHOX2B, GATA3, MEIS1, and SOX4, such that the first two are suppressed, and the latter two are more highly expressed. The findings also shed light on why some neuroblastomas are impervious to treatment with ATRA.
