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 (Couturier et al., 2020; Neftel et al., 2019;
Richards et al., 2021). The source of the dynamic reorganization within
the spatial context of these tumors remains elusive. Here, we
characterized glioblastomas in-depth 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
adapt 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.