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

Author:

Al-Dalahmah OsamaORCID,Argenziano Michael G.,Kannan AdithyaORCID,Mahajan Aayushi,Furnari Julia,Paryani Fahad,Boyett Deborah,Save Akshay,Humala Nelson,Khan Fatima,Li Juncheng,Lu Hong,Sun Yu,Tuddenham John F.ORCID,Goldberg Alexander R.ORCID,Dovas Athanassios,Banu Matei A.,Sudhakar Tejaswi,Bush Erin,Lassman Andrew B.,McKhann Guy M.,Gill Brian J. A.,Youngerman BrettORCID,Sisti Michael B.,Bruce Jeffrey N.ORCID,Sims Peter A.,Menon VilasORCID,Canoll PeterORCID

Abstract

AbstractGlioblastoma (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.

Funder

U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke

Publisher

Springer Science and Business Media LLC

Subject

General Physics and Astronomy,General Biochemistry, Genetics and Molecular Biology,General Chemistry,Multidisciplinary

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