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

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 transcrip-tional programs, confirming that environmental stress gives rise to selection pressure. A model of glioblas-toma stem cells implanted into human and rodent neocortical tissue mimicking various environments confirmed that transcriptional states originate from dynamic adaptation to various environments.

Automated summary

This study utilizes spatially resolved transcriptomics, metabolomics, and proteomics to characterize glioblastomas and uncover their spatial organization and adaptive mechanisms to inflammatory and metabolic stimuli. The integration of metabolic imaging and imaging mass cytometry reveals the interdependence between tumor and host in a locoregional manner, leading to spatially exclusive adaptive transcriptional programs. The findings confirm the importance of environmental stress in shaping glioblastoma subclones and their transcriptional programs.