Leveraging multi-omics to define the role of epigenetic regulation by PRC2 in Esthesioneuroblastoma

摘要 永久性嗅觉丧失是与嗅神经母细胞瘤（ENB）相关的常见疾病， 源自鼻子的嗅上皮。这是由于需要大量手术切除，无论 肿瘤分级因此，开发新的医学治疗策略对保护嗅觉是必要的 in this patient患者population人口.嗅上皮是产生神经元和支持神经元的神经源性小生境。 上皮细胞，以及正常上皮增殖的各种未分化阶段， 在ENB中观察到了发展。表观遗传调节剂多梳抑制复合物2（PRC2）具有以下功能： 与驱动全身干细胞龛中的增殖细胞状态有关。我们已经证明 PRC2对于嗅上皮中的基底细胞增殖至关重要，我们已经确定它在嗅上皮中表达。 在ENB中增殖细胞。由于ENB是一种罕见的肿瘤，机制生物学研究很少，没有细胞 线或鼠标模型存在。此外，大多数ENB不共享共同的驱动突变， 强调表观遗传调控的重要性。在这里，我建议利用新开发的多组学 研究PRC2在人ENB中的表达如何指定细胞状态并有助于肿瘤 增长我将对多种肿瘤进行单细胞染色质和转录组学检测，以确定 染色体可及性此外，我将使用人ENB样本的药理学试验来评估 对转录的下游影响。最后，空间转录组学将用于定义ENB细胞和 分子组成，包括PRC相关的表达，以及与正常嗅觉相比如何 上皮，以阐明ENB内肿瘤和免疫细胞之间的细胞信号传导动力学 微环境完成拟议的研究将确定ENB与 目标是确定新的药物靶点，从而提高生存率和气味的保存。总之， 本提案中概述的研究和培训计划与布拉德利博士的专家指导相结合 戈尔茨坦将为我提供严格的培训，使我能够在2010年成为一名成功的外科医生和科学家。 颅外科和前颅底外科。

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.