胶质母细胞瘤（GBM）是具有广泛肿瘤内异质性的侵袭性脑肿瘤，导致治疗抵抗性增加。GBM的空间特征描述可以为了解脑肿瘤微环境在调控肿瘤内异质性方面发挥作用提供见解。在这里，我们对小鼠和人类GBM微环境进行了空间转录组和单细胞分析，以解剖大脑不同解剖区域对GBM的影响。在同基因GBM小鼠模型中，空间转录组学显示，许多细胞外基质（ECM）分子，包括大卵泡素，在脑肿瘤始动细胞（BTIC）浸润的区域中升高。单细胞RNA测序和单细胞转座可及染色质分析使用测序显示，ECM分子根据其分化和细胞编程表型，由GBM细胞不同表达。给予外源性大卵泡素或过度表达大卵泡素导致BTIC增殖率更高，这与低密度脂蛋白受体相关蛋白6（LRP6）结合和Wnt/β-连环蛋白通路激活机理有关。大量表达大卵泡素的BTIC在小鼠颅内植入后发展成更大的肿瘤，并显示间充质表型。该研究揭示了GBM中ECM分子的空间异质性，并建议大卵泡素-LRP6轴可能是控制肿瘤生长的治疗靶点。对胶质母细胞瘤空间异质性的表征确定了大脑肿瘤起始细胞和肿瘤生长的调节因子，并可用作候选治疗干预措施以改善患者预后。©2023美国癌症研究协会。

Glioblastomas (GBM) are aggressive brain tumors with extensive intratumoral heterogeneity that contributes to treatment resistance. Spatial characterization of GBMs could provide insights into the role of the brain tumor microenvironment in regulating intratumoral heterogeneity. Here, we performed spatial transcriptomic and single-cell analyses of the mouse and human GBM microenvironment to dissect the impact of distinct anatomical regions of brains on GBM. In a syngeneic GBM mouse model, spatial transcriptomics revealed that numerous extracellular matrix (ECM) molecules, including biglycan, were elevated in areas infiltrated with brain tumor-initiating cells (BTIC). Single-cell RNA sequencing and single-cell assay for transposase-accessible chromatin using sequencing showed that ECM molecules were differentially expressed by GBM cells based on their differentiation and cellular programming phenotypes. Exogeneous biglycan or overexpression of biglycan resulted in a higher proliferation rate of BTICs, which was associated mechanistically with low-density lipoprotein receptor-related protein 6 (LRP6) binding and activation of the Wnt/β-catenin pathway. Biglycan-overexpressing BTICs developed into larger tumors and displayed mesenchymal phenotypes when implanted intracranially in mice. This study points to the spatial heterogeneity of ECM molecules in GBM and suggests that the biglycan-LRP6 axis could be a therapeutic target to curb tumor growth.Characterization of the spatial heterogeneity of glioblastoma identifies regulators of brain tumor-initiating cells and tumor growth that could serve as candidates for therapeutic interventions to improve the prognosis of patients.©2023 American Association for Cancer Research.