ABSTRACT Permanent smell loss is a common morbidity associated with esthesioneuroblastoma (ENB), a tumor thought to arise from the olfactory epithelium in the nose. This is due to necessity for bulk surgical resection, regardless of tumor grade. As such, the development of novel medical treatment strategies is necessary to preserve olfaction in this patient population. The olfactory epithelium is a neurogenic niche that produces neurons and supporting epithelial cells throughout life, and various undifferentiated stages of normal epithelial proliferation and development have been observed in ENB. The epigenetic regulator polycomb repressive complex 2 (PRC2) has been implicated in driving proliferative cell states in stem cell niches throughout the body. We have shown that PRC2 is crucial for basal cell proliferation in the olfactory epithelium, and we have identified that it is expressed in proliferating cells in ENB. Because ENB is a rare tumor, mechanistic biological studies are sparse, and no cell lines or mouse models exist. Furthermore, the majority of ENBs do not share common driver mutations, emphasizing the importance of epigenetic regulation. Here I propose to utilize newly-developed multi-omic studies to investigate how PRC2 expression in human ENB specifies cellular states and contributes to tumor growth. I will perform single cell chromatin and transcriptomic assays on multiple tumors to identify areas of chromosomal accessibility. Furthermore, I will use pharmacologic assays in human ENB samples to assess the downstream effects on transcription. Finally, spatial transcriptomics will be used to define ENB cellular and molecular composition, including PRC-associated expression, and how this compares to normal olfactory epithelium, to elucidate cellular signaling dynamics among tumor and immune cells within the ENB microenvironment. Completion of the proposed studies will define epigenetic drivers co-opted by ENB with the goal of identifying new druggable targets, allowing for improved survival and preservation of smell. Altogether, the research and training plan outlined in this proposal combined with expert mentorship from Dr. Bradley Goldstein will prepare me with the rigorous training necessary for a successful career as a surgeon-scientist in rhinology and anterior skull base surgery.