Re-convolving the compositional landscape of primary and recurrent glioblastoma reveals prognostic and targetable tissue states

• Published in: Nature communications Vol. 14; no. 1; p. 2586
• Main Authors: Al-Dalahmah, Osama, Argenziano, Michael G., Kannan, Adithya, Mahajan, Aayushi, Furnari, Julia, Paryani, Fahad, Boyett, Deborah, Save, Akshay, Humala, Nelson, Khan, Fatima, Li, Juncheng, Lu, Hong, Sun, Yu, Tuddenham, John F., Goldberg, Alexander R., Dovas, Athanassios, Banu, Matei A., Sudhakar, Tejaswi, Bush, Erin, Lassman, Andrew B., McKhann, Guy M., Gill, Brian J. A., Youngerman, Brett, Sisti, Michael B., Bruce, Jeffrey N., Sims, Peter A., Menon, Vilas, Canoll, Peter
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 04.05.2023; Nature Publishing Group; Nature Portfolio
• Subjects: 13; 14; 14/32; 49/91; 631/378/1689/1690; 631/67/1922; 631/67/327; 631/67/69; Astrocytes; Astrocytes - metabolism; Biosynthesis; Brain; Brain cancer; Brain Neoplasms - pathology; Cohabitation; Fatty acids; Gene sequencing; Glioblastoma; Glioblastoma - pathology; Glioma - genetics; Glioma cells; Humanities and Social Sciences; Humans; Macrophages; Metabolic pathways; Microglia; multidisciplinary; Myeloid cells; Nuclei (cytology); Prognosis; Science; Science (multidisciplinary); Subpopulations; Therapeutic targets; Tissues; Transcriptomics; Tumor microenvironment; Tumor Microenvironment - genetics; Tumors
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-023-38186-1

Glioblastoma (GBM) diffusely infiltrates the brain and intermingles with non-neoplastic brain cells, including astrocytes, neurons and microglia/myeloid cells. This complex mixture of cell types forms the biological context for therapeutic response and tumor recurrence. We used single-nucleus RNA sequencing and spatial transcriptomics to determine the cellular composition and transcriptional states in primary and recurrent glioma and identified three compositional ‘tissue-states’ defined by cohabitation patterns between specific subpopulations of neoplastic and non-neoplastic brain cells. These tissue-states correlated with radiographic, histopathologic, and prognostic features and were enriched in distinct metabolic pathways. Fatty acid biosynthesis was enriched in the tissue-state defined by the cohabitation of astrocyte-like/mesenchymal glioma cells, reactive astrocytes, and macrophages, and was associated with recurrent GBM and shorter survival. Treating acute slices of GBM with a fatty acid synthesis inhibitor depleted the transcriptional signature of this pernicious tissue-state. These findings point to therapies that target interdependencies in the GBM microenvironment. Glioblastoma (GBM) cells can infiltrate into the tumour microenvironment (TME) and contribute to recurrence. Here, the authors analyse primary and recurrent GBMs and their TME using single-nucleus and spatial transcriptomics, revealing tissue states defined by the combinations of neoplastic and non-neoplastic cells, which could be therapeutic targets.