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

ABSTRACT: Re-convolving the compositional landscape of primary and recurrent glioblastoma reveals prognostic and targetable tissue states [plateseq]

PROVIDER: PRJNA950052 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR24006600.fastq.gz	Fastqsanger.gz
	SRR24006601.fastq.gz	Fastqsanger.gz
	SRR24006602.fastq.gz	Fastqsanger.gz
	SRR24006603.fastq.gz	Fastqsanger.gz
	SRR24006604.fastq.gz	Fastqsanger.gz

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

Project description: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.

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

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

Project description: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.

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