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Spatial architecture of high-grade glioma reveals tumor heterogeneity within distinct domains

ABSTRACT: Spatial architecture of high-grade glioma reveals tumor heterogeneity within distinct domains

PROVIDER: PRJNA972273 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR24541800_1.fastq.gz	Fastqsanger.gz
	SRR24541800_2.fastq.gz	Fastqsanger.gz
	SRR24541900_1.fastq.gz	Fastqsanger.gz
	SRR24541900_2.fastq.gz	Fastqsanger.gz
	SRR24541801_1.fastq.gz	Fastqsanger.gz

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Spatial architecture of high-grade glioma reveals tumor heterogeneity within distinct domains

Project description:High-grade gliomas are aggressive primary brain cancers with poor response to standard regimens, driven by immense heterogeneity. In isocitrate dehydrogenase (IDH) wild-type high-grade glioma (glioblastoma, GBM), increased intra-tumoral heterogeneity is associated with more aggressive disease. Recently, spatial technologies have emerged to dissect this complex heterogeneity within the tumor ecosystem by preserving cellular organization in situ. Here, we construct a high- resolution molecular landscape of GBM and IDH-mutant high-grade glioma patient samples to investigate the cellular subtypes and spatial communities that compose high-grade glioma using digital spatial profiling and spatial molecular imaging. This uncovered striking diversity of the tumor and immune microenvironment, that is embodied by the heterogeneity of the inferred copy- number alterations in the tumor. Reconstructing the tumor architecture revealed brain-intrinsic niches, composed of tumor cells reflecting brain cell types and microglia; and brain-extrinsic niches, populated by mesenchymal tumor cells and monocytes. We further reveal that cellular communication in these niches is underpinned by specific ligand-receptor pairs. This primary study reveals high levels of intra-tumoral heterogeneity in high-grade gliomas, associated with a diverse immune landscape within spatially localized regions.

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Spatial architecture of high-grade glioma reveals tumor heterogeneity within distinct domains.

Project description:BackgroundHigh-grade gliomas (HGGs) are aggressive primary brain cancers with poor response to standard regimens, driven by immense heterogeneity. In isocitrate dehydrogenase (IDH) wild-type HGG (glioblastoma, GBM), increased intratumoral heterogeneity is associated with more aggressive disease.MethodsSpatial technologies can dissect complex heterogeneity within the tumor ecosystem by preserving cellular organization in situ. We employed GeoMx digital spatial profiling, CosMx spatial molecular imaging, Xenium in situ mapping and Visium spatial gene expression in experimental and validation patient cohorts to interrogate the transcriptional landscape in HGG.ResultsHere, we construct a high-resolution molecular map of heterogeneity in GBM and IDH-mutant patient samples to investigate the cellular communities that compose HGG. We uncovered striking diversity in the tumor landscape and degree of spatial heterogeneity within the cellular composition of the tumors. The immune distribution was diverse between samples, however, consistently correlated spatially with distinct tumor cell phenotypes, validated across tumor cohorts. Reconstructing the tumor architecture revealed two distinct niches, one composed of tumor cells that most closely resemble normal glial cells, associated with microglia, and the other niche populated by monocytes and mesenchymal tumor cells.ConclusionsThis primary study reveals high levels of intratumoral heterogeneity in HGGs, associated with a diverse immune landscape within spatially localized regions.

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Relative spatial heterogeneity revealed by transcriptional profiling of multi-region high-grade glioma samples

Project description:Affymetrix GeneChipÂ® Human Genome U133 Plus 2.0 Array profiling of 20 primary, multi-region high-grade glioma samples. Total RNA was extracted from primary high-grade glioma samples and hybridized to GeneChipÂ® Human Genome U133 Plus 2.0 Array according to the manufacturer's instructions.

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