PDF(Pubmed)
Abstract：
The olfactory epithelium undergoes neuronal regeneration from basal stem cells and is susceptible to olfactory neuroblastoma (ONB), a rare tumor of unclear origins. Employing alterations in Rb1/Trp53/Myc (RPM), we establish a genetically engineered mouse model of high-grade metastatic ONB exhibiting a NEUROD1+ immature neuronal phenotype. We demonstrate that globose basal cells (GBCs) are a permissive cell of origin for ONB and that ONBs exhibit cell fate heterogeneity that mimics normal GBC developmental trajectories. ASCL1 loss in RPM ONB leads to emergence of non-neuronal histopathologies, including a POU2F3+ microvillar-like state. Similar to small-cell lung cancer (SCLC), mouse and human ONBs exhibit mutually exclusive NEUROD1 and POU2F3-like states, an immune-cold tumor microenvironment, intratumoral cell fate heterogeneity comprising neuronal and non-neuronal lineages, and cell fate plasticity-evidenced by barcode-based lineage tracing and single-cell transcriptomics. Collectively, our findings highlight conserved similarities between ONB and neuroendocrine tumors with significant implications for ONB classification and treatment.
摘要：
嗅觉上皮从基底干细胞经历神经元再生，并且对嗅觉神经母细胞瘤（ONB）敏感，一种起源不明的罕见肿瘤.在Rb1/Trp53/Myc(RPM)中使用改变，我们建立了表现出NEUROD1+未成熟神经元表型的高度转移性ONB的基因工程小鼠模型。我们证明球状基底细胞（GBC）是ONB的允许起源细胞，并且ONB表现出细胞命运异质性，可以模拟正常的GBC发育轨迹。RPMONB中的ASCL1丢失导致非神经元组织病理学的出现，包括POU2F3+微型化状态。类似于小细胞肺癌（SCLC），小鼠和人类ONB表现出互斥的NEUROD1和POU2F3样状态，免疫冷肿瘤微环境，肿瘤内细胞命运异质性包括神经元和非神经元谱系，和细胞命运可塑性-通过基于条形码的谱系追踪和单细胞转录组学证明。总的来说，我们的研究结果强调了ONB和神经内分泌肿瘤之间的保守相似性,对ONB的分类和治疗具有重要意义.
