加拿大多伦多大学Peter B. Dirks等研究人员合作发现，神经胶质瘤发生可模拟由神经脊样细胞协调的损伤反应。相关论文于2025年1月1日在线发表在《自然》杂志上。

为了探讨胶质瘤发生的早期步骤，研究人员在肿瘤小鼠模型中使用条件性基因删除和谱系追踪，结合序列磁共振成像（MRI）来启动并密切追踪肿瘤形成过程。研究人员在多个阶段（包括肿瘤第一次出现可见异常之前、第一次可见病变时以及肿瘤生长的各个阶段）分离了标记和未标记的细胞，并对每个阶段的细胞进行单细胞谱系分析。

研究人员识别出一种具有神经脊样基因表达特征的恶性细胞状态，在肿瘤生长的早期阶段高度丰富，但在晚期阶段相对减少。基于拷贝数变化的基因组分析表明，这些神经脊样状态作为异质性克隆层级的一部分，随肿瘤生长而进化。通过探讨正常小鼠大脑受伤后的反应，研究人员发现有类似的细胞特征在受伤后出现，并随着时间的推移消失，提示肿瘤发生过程中激活了一种损伤反应程序。

事实上，这些实验揭示了一种非恶性的损伤样微环境，它是在大脑中通过启动癌基因激活大脑前体细胞后形成的。总体而言，该研究为胶质母细胞瘤的早期阶段提供了新的见解，并识别了一种独特的细胞状态以及与早期肿瘤形成相关的损伤反应程序。这些发现对胶质母细胞瘤的治疗具有重要意义，并为早期诊断和预防该疾病提供了新的可能性。

据介绍，胶质母细胞瘤是一种无法治愈的脑部恶性肿瘤。在临床诊断时，这些肿瘤已经表现出一定程度的基因和细胞异质性，这使得揭示肿瘤发生机制的线索变得非常有限。

附：英文原文

Title: Gliomagenesis mimics an injury response orchestrated by neural crest-like cells

Author: Hamed, Akram A., Hua, Kui, Trinh, Quang M., Simons, Benjamin D., Marioni, John C., Stein, Lincoln D., Dirks, Peter B.

Issue&Volume: 2025-01-01

Abstract: Glioblastoma is an incurable brain malignancy. By the time of clinical diagnosis, these tumours exhibit a degree of genetic and cellular heterogeneity that provides few clues to the mechanisms that initiate and drive gliomagenesis1,2. Here, to explore the early steps in gliomagenesis, we utilized conditional gene deletion and lineage tracing in tumour mouse models, coupled with serial magnetic resonance imaging, to initiate and then closely track tumour formation. We isolated labelled and unlabelled cells at multiple stages—before the first visible abnormality, at the time of the first visible lesion, and then through the stages of tumour growth—and subjected cells of each stage to single-cell profiling. We identify a malignant cell state with a neural crest-like gene expression signature that is highly abundant in the early stages, but relatively diminished in the late stage of tumour growth. Genomic analysis based on the presence of copy number alterations suggests that these neural crest-like states exist as part of a heterogeneous clonal hierarchy that evolves with tumour growth. By exploring the injury response in wounded normal mouse brains, we identify cells with a similar signature that emerge following injury and then disappear over time, suggesting that activation of an injury response program occurs during tumorigenesis. Indeed, our experiments reveal a non-malignant injury-like microenvironment that is initiated in the brain following oncogene activation in cerebral precursor cells. Collectively, our findings provide insight into the early stages of glioblastoma, identifying a unique cell state and an injury response program tied to early tumour formation. These findings have implications for glioblastoma therapies and raise new possibilities for early diagnosis and prevention of disease.

DOI: 10.1038/s41586-024-08356-2

Source: https://www.nature.com/articles/s41586-024-08356-2