空间分辨多组学解析胶质母细胞瘤中肿瘤-宿主的双向相互依赖关系。

Spatially resolved multi-omics deciphers bidirectional tumor-host interdependence in glioblastoma.

机构信息

Microenvironment and Immunology Research Laboratory, Medical Center - University of Freiburg, Freiburg, Germany; Department of Neurosurgery, Medical Center - University of Freiburg, Freiburg, Germany; Faculty of Medicine, University of Freiburg, Freiburg, Germany; Translational NeuroOncology Research Group, Medical Center - University of Freiburg, Freiburg, Germany; Freiburg Institute for Advanced Studies (FRIAS), University of Freiburg, Freiburg, Germany; Center of Advanced Surgical Tissue Analysis (CAST), University of Freiburg, Freiburg, Germany.

出版信息

Cancer Cell. 2022 Jun 13;40(6):639-655.e13. doi: 10.1016/j.ccell.2022.05.009.

DOI:10.1016/j.ccell.2022.05.009

PMID:35700707

Abstract

Glioblastomas are malignant tumors of the central nervous system hallmarked by subclonal diversity and dynamic adaptation amid developmental hierarchies. The source of dynamic reorganization within the spatial context of these tumors remains elusive. Here, we characterized glioblastomas by spatially resolved transcriptomics, metabolomics, and proteomics. By deciphering regionally shared transcriptional programs across patients, we infer that glioblastoma is organized by spatial segregation of lineage states and adapts to inflammatory and/or metabolic stimuli, reminiscent of the reactive transformation in mature astrocytes. Integration of metabolic imaging and imaging mass cytometry uncovered locoregional tumor-host interdependence, resulting in spatially exclusive adaptive transcriptional programs. Inferring copy-number alterations emphasizes a spatially cohesive organization of subclones associated with reactive transcriptional programs, confirming that environmental stress gives rise to selection pressure. A model of glioblastoma stem cells implanted into human and rodent neocortical tissue mimicking various environments confirmed that transcriptional states originate from dynamic adaptation to various environments.

摘要

胶质母细胞瘤是中枢神经系统的恶性肿瘤，其特征是在发育层次结构中存在亚克隆多样性和动态适应。这些肿瘤空间背景下的动态重组的来源仍然难以捉摸。在这里，我们通过空间分辨转录组学、代谢组学和蛋白质组学对胶质母细胞瘤进行了表征。通过破译跨患者的区域性共享转录程序，我们推断胶质母细胞瘤是由谱系状态的空间隔离组织起来的，并对炎症和/或代谢刺激做出反应，类似于成熟星形胶质细胞的反应性转化。代谢成像和成像质谱细胞术的整合揭示了局部肿瘤-宿主的相互依存关系，导致空间上独特的适应性转录程序。推断拷贝数改变强调了与反应性转录程序相关的亚克隆的空间一致组织，证实环境压力产生选择压力。将胶质母细胞瘤干细胞植入到模拟各种环境的人类和啮齿动物新皮质组织中的模型证实，转录状态源自对各种环境的动态适应。