Re-convolving the compositional landscape of primary and recurrent glioblastoma reveals prognostic and targetable tissue states [plateseq]
Glioblastoma is an aggressive diffusely infiltrating neoplasm that spreads beyond surgical resection margins, where it intermingles with non-neoplastic brain cells. This complex microenvironment harbouring infiltrating glioma and non-neoplastic brain cells is the origin of tumor recurrence. Thus, understanding the cellular and molecular features of the glioma microenvironment is therapeutically and prognostically important. Here, we used single-nucleus RNA sequencing (snRNAseq) of primary and recurrent glioma to define three compositional 'tissue-states' rooted in cohabitation of cell-types and transcriptional states. These comprise a state featuring A) minimally infiltrated-brain, B) reactive inflamed infiltrated tissue, and C) cellular tumor. Spatial transcriptomics confirmed that the cell-types and transcriptomics states which compositionally cohabitate indeed do colocalize in space. Tissue states are clinically significant because they correlate with radiographic, histopathologic, and prognostic features. We found that in addition to enrichment of tissue state B signature, enrichment of both neoplastic and non-neoplastic cell-type gene signatures in tissue state B correlated with decreased survival. Importantly, we found that our compositionally defined tissue states are enriched in distinct metabolic pathways. One such pathway is fatty acid biosynthesis, which was enriched in tissue state B – a state enriched in recurrent glioblastoma and composed of astrocyte-like/mesenchymal glioma cells, reactive astrocytes resembling those seen in neurodegeneration, and monocyte-like myeloid cells. We discovered that targeting fatty acid synthesis was sufficient to deplete the transcriptional signature of tissue state B. Our findings define a novel compositional approach to the glioma infiltrated tissue which allows us to discover prognostic and targetable features, paving the way to new mechanistic and therapeutic discoveries. Overall design: Comparative gene expression and molecular analysis on GBM tissue that are primary glioma versus a recurrent glioma.