Glioblastoma (GBM) is the most common primary malignant cancer of the central nervous system. Insufficient oxygenation (hypoxia) has been linked to GBM invasion and aggression, leading to poor patient outcomes. Hypoxia induces gene expression for cellular adaptations. However, GBM is characterized by high intertumoral (molecular subtypes) and intratumoral heterogeneity (cell states), and it is not well understood to what extent hypoxia triggers patient-specific gene responses and cellular diversity in GBM. Here, we surveyed eight patient-derived GBM stem cell lines for invasion phenotypes in 3D culture, which identified two GBM lines showing increased invasiveness in response to hypoxia. RNA-seq analysis of the two patient GBM lines revealed a set of shared hypoxia response genes concerning glucose metabolism, angiogenesis, and autophagy, but also a large set of patient-specific hypoxia-induced genes featuring cell migration and anti-inflammation, highlighting intertumoral diversity of hypoxia responses in GBM. We further applied the Shared GBM Hypoxia gene signature to single cell RNA-seq datasets of glioma patients, which showed that hypoxic cells displayed a shift towards mesenchymal-like (MES) and astrocyte-like (AC) states. Interestingly, in response to hypoxia, tumor cells in IDH-mutant gliomas displayed a strong shift to the AC state, whereas tumor cells in IDH-wildtype gliomas mainly shifted to the MES state. This distinct hypoxia response of IDH-mutant gliomas may contribute to its more favorable prognosis. Our transcriptomic studies provide a basis for future approaches to better understand the diversity of hypoxic niches in gliomas.

胶质母细胞瘤（GBM）是中枢神经系统最常见的原发性恶性肿瘤。氧合不足（缺氧）与 GBM 侵袭和攻击有关，导致患者预后不佳。缺氧会诱导细胞适应的基因表达。然而，GBM 的特点是瘤间（分子亚型）和瘤内异质性（细胞状态）较高，目前尚不清楚缺氧在多大程度上触发 GBM 中患者特异性基因反应和细胞多样性。在这里，我们调查了 8 个患者来源的 GBM 干细胞系在 3D 培养中的侵袭表型，其中确定了两个 GBM 系显示出对缺氧反应增加的侵袭性。对两个患者 GBM 系的 RNA-seq 分析揭示了一组与葡萄糖代谢、血管生成和自噬相关的共有缺氧反应基因，而且还揭示了一大组患者特异性缺氧诱导的基因，其特征是细胞迁移和抗炎，突出了肿瘤间的相互作用GBM 缺氧反应的多样性。我们进一步将共享 GBM 缺氧基因特征应用于神经胶质瘤患者的单细胞 RNA-seq 数据集，结果表明缺氧细胞表现出向间充质样 (MES) 和星形胶质细胞样 (AC) 状态的转变。有趣的是，为了应对缺氧，IDH突变型神经胶质瘤中的肿瘤细胞表现出向AC状态的强烈转变，而IDH野生型神经胶质瘤中的肿瘤细胞主要向MES状态转变。 IDH 突变神经胶质瘤的这种独特的缺氧反应可能有助于其更良好的预后。我们的转录组研究为未来更好地了解神经胶质瘤缺氧生态位的多样性提供了基础。