Department of Clinical Neurosciences, University of Calgary, Calgary, Alberta, Canada.
Hotchkiss Brain Institute, University of Calgary, Calgary, Alberta, Canada.
Cancer Res. 2023 May 15;83(10):1725-1741. doi: 10.1158/0008-5472.CAN-22-3004.
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.
胶质母细胞瘤（GBM）是一种侵袭性脑肿瘤，具有广泛的肿瘤内异质性，导致治疗耐药。GBM 的空间特征可以深入了解脑肿瘤微环境在调节肿瘤内异质性中的作用。在这里，我们对小鼠和人类 GBM 微环境进行了空间转录组学和单细胞分析，以剖析不同脑区对 GBM 的影响。在同源性 GBM 小鼠模型中，空间转录组学显示，大量细胞外基质（ECM）分子，包括 biglycan，在脑肿瘤起始细胞（BTIC）浸润的区域中升高。单细胞 RNA 测序和单细胞测定转座酶可及染色质测序显示，基于其分化和细胞编程表型，GBM 细胞对 ECM 分子的表达存在差异。外源性 biglycan 或 biglycan 的过表达导致 BTIC 的增殖率更高，其机制与低密度脂蛋白受体相关蛋白 6（LRP6）结合和 Wnt/β-连环蛋白通路的激活有关。在小鼠颅内植入时，过表达 biglycan 的 BTIC 形成更大的肿瘤，并表现出间充质表型。这项研究指出了 GBM 中 ECM 分子的空间异质性，并表明 biglycan-LRP6 轴可能是抑制肿瘤生长的治疗靶点。
胶质母细胞瘤空间异质性的特征确定了脑肿瘤起始细胞和肿瘤生长的调节剂，这些调节剂可能成为改善患者预后的治疗干预候选物。
