Integrative spatial analysis reveals a multi-layered organization of glioblastoma

Cell. 2024 May 9;187(10):2485-2501.e26. doi: 10.1016/j.cell.2024.03.029. Epub 2024 Apr 22.

Abstract

Glioma contains malignant cells in diverse states. Here, we combine spatial transcriptomics, spatial proteomics, and computational approaches to define glioma cellular states and uncover their organization. We find three prominent modes of organization. First, gliomas are composed of small local environments, each typically enriched with one major cellular state. Second, specific pairs of states preferentially reside in proximity across multiple scales. This pairing of states is consistent across tumors. Third, these pairwise interactions collectively define a global architecture composed of five layers. Hypoxia appears to drive the layers, as it is associated with a long-range organization that includes all cancer cell states. Accordingly, tumor regions distant from any hypoxic/necrotic foci and tumors that lack hypoxia such as low-grade IDH-mutant glioma are less organized. In summary, we provide a conceptual framework for the organization of cellular states in glioma, highlighting hypoxia as a long-range tissue organizer.

Keywords: glioblastoma; glioma; hypoxia; intratumor heterogeneity; spatial proteomics; spatial transcriptomics.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural

MeSH terms

  • Brain Neoplasms* / genetics
  • Brain Neoplasms* / metabolism
  • Brain Neoplasms* / pathology
  • Gene Expression Regulation, Neoplastic
  • Glioblastoma* / genetics
  • Glioblastoma* / metabolism
  • Glioblastoma* / pathology
  • Humans
  • Isocitrate Dehydrogenase / genetics
  • Isocitrate Dehydrogenase / metabolism
  • Proteomics
  • Spatial Analysis
  • Transcriptome / genetics
  • Tumor Microenvironment

Substances

  • Isocitrate Dehydrogenase