Spatial and single-cell characterization of human glioblastoma tumor microenvironment reveals malignant cellular communities.

1.논문제목: Spatial and single-cell characterization of human glioblastoma tumor microenvironment reveals malignant cellular communities.

2.저자명: Jun Lin, Chunpeng Chen, Shouzhen Li, Liu Chen, Minghao Fang, Shuqi Fu, Kaixing Chen, Hao Xu, Fenghuan Zhang, Rirui Wang, Chen Jiang, Meifang Tang, Zitian Liu, Shuyan Wang, Ke Liu, Chaoshi Niu, Bin Li, Xu Liu, Chuandong Cheng, Ai-Hui Tang & Kun Qu

3.발행일: Nature neuroscience, 16 April 2026

4.DOI: https://doi.org/10.1038/s41593-026-02265-5

5.Abstract: Understanding the complex cellular and spatial organization of glioblastoma (GBM) and its microenvironment is crucial for improving diagnosis and treatment. Here we integrated 121 spatial transcriptomics, single-cell RNA sequencing, single-cell assay for transposase-accessible chromatin using sequencing and patch sequencing profiles from 100 patients to characterize primary GBM tissue. We identified four malignant cellular communities that exhibited consistent patterns of cell-type compositions, gene expression and intercellular interactions across patients. We identified two subpopulations of mesenchymal-like (MES-like) tumor cells: MES-Hyp, colocalized with monocyte-derived brain macrophages in hypoxic regions; and MES-Ast, associated with endothelial cells, pericytes and vascular smooth muscle cells. We also predicted and experimentally verified cell subtypes and ligand–receptor pairs involved in intercellular communications in each cellular community. Furthermore, patch sequencing analysis revealed that synaptic connections with glioma cells were predominantly formed between neurons and oligodendrocyte-progenitor-like tumor cells. Overall, our study provides insights into the spatial organization and intercellular communication in GBM, offering potential therapeutic targets.

6.한글 초록: 본 연구는 교모세포종 (GBM)의 복잡한 종양 미세환경을 이해하기 위해 단일세포 전사체, 공간 전사체, 크로마틴 접근성 데이터 및 patch-seq을 통합 분석함. 총 100명의 환자에서 획득한 121개의 데이터셋을 기반으로 분석한 결과, GBM 조직은 세포 구성, 유전자 발현, 세포 간 상호작용 패턴이 일관되게 나타나는 네 가지 악성 세포 커뮤니티 (cellular communities, CCs)로 구성됨을 확인함. 특히 mesenchymal-like 종양 세포는 두 개의 아형 (MES-Hyp, MES-Ast)으로 구분되며, 각각 저산소 환경 및 혈관 환경과 밀접하게 연관되어 있었음. 또한 종양 세포와 면역세포, 혈관세포, 신경세포 간의 상호작용에 관여하는 ligand-receptor 쌍을 규명하였고, OPC-like 종양 세포가 뉴런과 직접적인 시냅스 연결을 형성함을 실험적으로 검증함. 본 연구는 GBM의 공간적 조직 구조와 세포 간 상호작용을 체계적으로 규명하고 새로운 치료 타겟을 제시함.

7.한글 논문 요약본:

7-1 Introduction: GBM은 성인에서 가장 흔한 악성 뇌종양으로, 높은 이질성과 복잡한 종양 미세환경을 특징으로 함. 기존 연구를 통해 GBM은 mesenchymal-like, astrocyte-like, oligodendrocyte progenitor-like, neural progenitor-like 등의 다양한 종양 세포 아형으로 구성됨이 알려져 있으나, 이러한 세포들이 실제 조직 내에서 어떻게 공간적으로 배열되고 상호작용하는지는 충분히 규명되지 않음. 특히 종양 관련 대식세포와 종양 세포 간 상호작용, 그리고 뉴런과 종양 세포 간의 시냅스 연결이 종양 성장에 중요한 역할을 한다는 보고가 있으나, 이러한 상호작용이 특정 공간적 맥락에서 어떻게 조직화되는지는 명확하지 않음. 이에 본 연구는 단일세포 분석과 공간 전사체 분석을 통합하여 GBM의 공간적 구조를 체계적으로 규명하고, 세포 간 상호작용 네트워크를 이해하는 것을 목적으로 함.  

7-2 Methods: 본 연구에서는 100명의 GBM 환자로부터 수집된 데이터를 활용하여 다중 오믹스 분석을 수행함. 단일세포 RNA 시퀀싱 (scRNA-sequencing), 단일세포 ATAC 시퀀싱 (scATAC-seq), 공간 전사체 (10x visium), in situ hybridization (ISH), 그리고 patch-seq 데이터를 통합 분석함. scRNA-seq 데이터를 기반으로 세포 유형을 분류하고, cell2location 알고리즘을 이용하여 공간 전사체 데이터에서 각 위치의 세포 구성을 추정함. 이후 SPACEL 분석을 통해 공통적인 공간 도메인을 도출하고 이를 기반으로 네 가지 cellular community를 정의함. 또한 Tangram을 활용하여 단일세포 데이터를 공간 데이터에 매핑하였으며, pseudotime 분석을 통해 종양 세포 상태 전이를 분석함. 세포 간 상호작용은 ligand-receptor 분석을 통해 예측하였고, phenocycler 및 ISH를 통해 공간적 공존 및 상호작용을 실험적으로 검증함. 추가적으로 patch-seq을 이용하여 종양 세포와 뉴런 간의 전기생리학적 연결을 확인함.

7-3 Results:

7-3-1) GBM의 공간 구조: 4개의 cellular communities: 분석 결과, GBM 조직은 반복적으로 나타나는 네 가지 공간적 커뮤니티로 구성됨을 확인함. CC-1: 저산소 환경, MES-like 종양세포 및 면역세포 풍부/ CC-2: 혈관 및 기질 구성, MES-Ast 세포 우세/ CC-3: 뉴런과 종양세포가 밀접한 영역/ CC-4: AC-like 세포 중심 영역. 이는 GBM이 무질서한 구조가 아니라 기능적으로 조직된 공간 구조를 가진다는 것을 의미함.

7-3-2) MES-like 종양 세포의 이질성: MES-like 세포는 두 가지 아형으로 구분됨. MES-Hyp는 저산소 관련 유전자 발현하고 면역세포 유입을 유도함. MES-Ast는 ECM 및 collagen 관련 유전자 발현하고 혈관 형성과 관련됨. 이 두 아형은 서로 다른 공간적 위치와 기능을 가지며 종양 진행에 기여함.

7-3-3) 종양 세포 상태 전이: pseudotime 분석 결과, AC-like → MES-Ast → MES-Hyp 방향의 전이가 확인되었으며 저산소 환경이 이러한 전이를 유도하는 주요 요인으로 나타남.

7-3-4) 면역세포 재프로그래밍: monocyte는 특정 전사인자 (SREBF1, MAFB 등)에 의해 종양 촉진형 TAM으로 분화되며, 특히 TAM5-GPNMB 아형이 종양 진행에 중요한 역할을 함.

7-3-5) 세포 간 상호작용 네트워크: 각 CC에서 특이적인 ligand-receptor 상호작용이 관찰됨. CC-1: 종양세포-면역세포 상호작용 (VEGF signaling), CC-2: 종양세포-혈관세포 상호작용 (TGFß, collagen signaling), CC-3: 뉴런-종양세포 상호작용 (synaptic signaling)

7-3-6) 뉴런-종양 시냅스 형성: patch-seq 분석을 통해 OPC-like 종양 세포가 뉴런과 직접적인 시냅스 연결을 형성함이 확인되었으며, 이러한 상호작용이 종양세포 증식과 관련됨이 나타남.

8.대표 Figure: Fig1. Identification and cellular composition of four CCs.