美国杜克大学Trudy G. Oliver和Bradley J. Goldstein共同合作，近期取得重要工作进展。他们研究提出嗅觉神经母细胞瘤模拟小细胞肺癌的分子异质性和谱系轨迹。相关研究成果2024年5月23日在线发表于《癌细胞》杂志上。

据介绍，嗅上皮经历基底干细胞的神经元再生，易受嗅觉神经母细胞瘤（ONB）的影响，这是一种起源不明的罕见肿瘤。

利用Rb1/Trp53/Myc（RPM）的改变，研究人员建立了一个高级别转移性ONB的基因工程小鼠模型，该模型表现出NEUROD1⁺未成熟神经元表型。研究人员证明，球状基底细胞（GBC）是ONB的允许来源细胞，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的缺失导致非神经元组织病理学的出现，包括POU2F3⁺微绒毛样状态。类似于小细胞肺癌癌症（SCLC），小鼠和人ONB表现出相互排斥的NEUROD1和POU2F3样状态、免疫冷肿瘤微环境、包括神经元和非神经元谱系的肿瘤内细胞命运异质性，以及通过基于条形码的谱系追踪和单细胞转录组学提供的细胞命运可塑性。

总之，这一研究结果强调了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。

附：英文原文

Title: Olfactory neuroblastoma mimics molecular heterogeneity and lineage trajectories of small-cell lung cancer

Author: John B. Finlay, Abbie S. Ireland, Sarah B. Hawgood, Tony Reyes, Tiffany Ko, Rachelle R. Olsen, Ralph Abi Hachem, David W. Jang, Diana Bell, Joseph M. Chan, Bradley J. Goldstein, Trudy G. Oliver

Issue&Volume: 2024-05-23

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.

DOI: 10.1016/j.ccell.2024.05.003

Source: https://www.cell.com/cancer-cell/fulltext/S1535-6108(24)00164-8