Single-nucleus and spatial landscape of the sub-ventricular zone in human glioblastoma

Glioblastoma (GBM) clinical management is challenging due to its heterogeneous nature, invasive potential, and poor response to radio- and chemo-therapy. As a result, GBM inevitably recurs and only a minority of patients survive 5 years post-diagnosis. We were the first to show that in the majority of GBM patients, the sub-ventricular zone (SVZ) of the lateral ventricles is a reservoir of cancer stem-like cells (CSCs) that show distinct patterns of treatment resistance when compared to matched CSCs from the tumor mass and contribute to the seeding of the recurrent tumor. However, the sampling and the characterization of the SVZ in GBM patients pose several challenges, as this area is extremely small and needs to be objectively identified during tumor surgical resection. To overcome this challenge, by using our fluorescence-guided multiple sampling scheme, we built a single-nucleus RNA-sequencing-based microenvironment landscape of the SVZ in GBM patients (T_SVZ). By performing a systematic comparison with tumor mass (T_Mass) samples isolated from the same patients and using two histologically normal SVZ (N_SVZ) samples through a number of computational tools and experimental methods, we identified novel therapeutic vulnerabilities in the T_SVZ of GBM patients.

胶质母细胞瘤（Glioblastoma, GBM）因具有异质性、侵袭性，且对放疗与化疗应答不佳，其临床管理极具挑战。因此，GBM不可避免地会发生复发，确诊后仅少数患者可存活5年以上。本团队首次证实，在多数GBM患者中，侧脑室室管膜下区（sub-ventricular zone, SVZ）是癌干细胞样细胞（cancer stem-like cells, CSCs）的储存库；相较于来自肿瘤实体瘤的匹配癌干细胞样细胞，这类细胞呈现独特的治疗耐药模式，并参与复发性肿瘤的定植。然而，GBM患者的SVZ取样与表征面临诸多挑战：该区域体积极小，且需在肿瘤手术切除过程中被客观识别。为克服这一难题，本团队采用自主建立的荧光引导多取样方案，构建了基于单细胞核RNA测序（single-nucleus RNA-sequencing）的GBM患者SVZ微环境图谱（T_SVZ）。随后，通过与同一患者来源的肿瘤实体瘤（tumor mass, T_Mass）样本开展系统性比对，并结合两份组织学正常的室管膜下区（histologically normal SVZ, N_SVZ）样本，借助一系列计算工具与实验方法，本团队在GBM患者的T_SVZ中鉴定出全新的治疗易感靶点。