Glioblastoma remains one of the deadliest brain malignancies. First-line therapy consists of maximal surgical tumor resection, accompanied by chemotherapy and radiotherapy. Malignant cells escape surgical resection by migrating into the surrounding healthy brain tissue, where they give rise to the recurrent tumor. Based on gene expression, tumor cores can be subtyped into mesenchymal, proneural, and classical tumors, each being associated with differences in genetic alterations and cellular composition. In contrast, the adjacent brain parenchyma where infiltrating malignant cells escape surgical resection is less characterized in patients. Using spatial transcriptomics (n = 11), we show that malignant cells within proneural or mesenchymal tumor cores display spatially organized differences in gene expression, although such differences decrease within the infiltrated brain tissue. Malignant cells residing in infiltrated brain tissue have increased expression of genes related to neurodevelopmental pathways and glial cell differentiation. Our findings provide an updated view of the spatial landscape of glioblastomas and further our understanding of the malignant cells that infiltrate the healthy brain, providing new avenues for the targeted therapy of these cells after surgical resection.

胶质母细胞瘤仍然是最致命的脑恶性肿瘤之一。一线治疗包括最大程度的手术肿瘤切除，并伴有化疗和放疗。恶性细胞通过迁移到周围的健康脑组织来逃避手术切除，在那里它们会产生复发性肿瘤。根据基因表达，肿瘤核心可分为间充质肿瘤、神经肿瘤和经典肿瘤，每一种都与遗传改变和细胞组成的差异有关。相比之下，浸润性恶性细胞逃避手术切除的邻近脑实质在患者中的特征较少。使用空间转录组学 （n = 11），我们表明前神经或间充质肿瘤核心内的恶性细胞在基因表达上表现出空间组织上的差异，尽管这种差异在浸润的脑组织内减少。驻留在浸润脑组织中的恶性细胞与神经发育途径和神经胶质细胞分化相关的基因表达增加。我们的研究结果为胶质母细胞瘤的空间景观提供了更新的观点，并进一步加深了我们对浸润健康大脑的恶性细胞的理解，为手术切除后这些细胞的靶向治疗提供了新的途径。