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

Osama Al-Dalahmah (), Michael G. Argenziano, Adithya Kannan, Aayushi Mahajan, Julia Furnari, Fahad Paryani, Deborah Boyett, Akshay Save, Nelson Humala, Fatima Khan, Juncheng Li, Hong Lu, Yu Sun, John F. Tuddenham, Alexander R. Goldberg, Athanassios Dovas, Matei A. Banu, Tejaswi Sudhakar, Erin Bush, Andrew B. Lassman, Guy M. McKhann, Brian J. A. Gill, Brett Youngerman, Michael B. Sisti, Jeffrey N. Bruce, Peter A. Sims, Vilas Menon () and Peter Canoll ()
Additional contact information
Osama Al-Dalahmah: Columbia University Vagelos College of Physicians and Surgeons (VP&S)
Michael G. Argenziano: Columbia University Vagelos College of Physicians and Surgeons (VP&S)
Adithya Kannan: Columbia University Vagelos College of Physicians and Surgeons (VP&S)
Aayushi Mahajan: Columbia University Vagelos College of Physicians and Surgeons (VP&S)
Julia Furnari: Columbia University Vagelos College of Physicians and Surgeons (VP&S)
Fahad Paryani: Columbia University Vagelos College of Physicians and Surgeons (VP&S)
Deborah Boyett: Columbia University Vagelos College of Physicians and Surgeons (VP&S)
Akshay Save: Columbia University Vagelos College of Physicians and Surgeons (VP&S)
Nelson Humala: Columbia University Irving Medical Center
Fatima Khan: Columbia University Vagelos College of Physicians and Surgeons (VP&S)
Juncheng Li: Columbia University Vagelos College of Physicians and Surgeons (VP&S)
Hong Lu: Columbia University Vagelos College of Physicians and Surgeons (VP&S)
Yu Sun: Columbia University Vagelos College of Physicians and Surgeons (VP&S)
John F. Tuddenham: Columbia University Vagelos College of Physicians and Surgeons (VP&S)
Alexander R. Goldberg: Columbia University Vagelos College of Physicians and Surgeons (VP&S)
Athanassios Dovas: Columbia University Vagelos College of Physicians and Surgeons (VP&S)
Matei A. Banu: Columbia University Vagelos College of Physicians and Surgeons (VP&S)
Tejaswi Sudhakar: Columbia University Vagelos College of Physicians and Surgeons (VP&S)
Erin Bush: Columbia University Vagelos College of Physicians and Surgeons (VP&S)
Andrew B. Lassman: Columbia University Irving Medical Center
Guy M. McKhann: Columbia University Irving Medical Center
Brian J. A. Gill: Columbia University Irving Medical Center
Brett Youngerman: Columbia University Irving Medical Center
Michael B. Sisti: Columbia University Irving Medical Center
Jeffrey N. Bruce: Columbia University Irving Medical Center
Peter A. Sims: Columbia University Irving Medical Center
Vilas Menon: Columbia University Vagelos College of Physicians and Surgeons (VP&S)
Peter Canoll: Columbia University Vagelos College of Physicians and Surgeons (VP&S)

Nature Communications, 2023, vol. 14, issue 1, 1-18

Abstract: Abstract 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.

Date: 2023
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DOI: 10.1038/s41467-023-38186-1

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