嗅上皮经历基底干细胞的神经元再生，并且容易罹患嗅神经母细胞瘤（ONB），这是一种来源不明的罕见肿瘤。利用 Rb1/Trp53/Myc (RPM) 的改变，我们建立了一种具有 NEUROD1 不成熟神经元表型的高级别转移性 ONB 基因工程小鼠模型。我们证明球形基底细胞（GBC）是 ONB 的允许起源细胞，并且 ONB 表现出模仿正常 GBC 发育轨迹的细胞命运异质性。 RPM ONB 中 ASCL1 缺失会导致非神经元组织病理学的出现，包括 POU2F3 微绒毛样状态。与小细胞肺癌 (SCLC) 类似，小鼠和人类 ONB 表现出相互排斥的 NEUROD1 和 POU2F3 样状态、免疫冷肿瘤微环境、包含神经元和非神经元谱系的瘤内细胞命运异质性以及细胞命运可塑性证据通过基于条形码的谱系追踪和单细胞转录组学。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保守的相似性，对 ONB 分类和治疗具有重要意义。版权所有 © 2024 作者。由爱思唯尔公司出版。保留所有权利。

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.Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.