Spatial transcriptomics reveals niche-specific enrichment and vulnerabilities of radial glial stem-like cells in malignant gliomas

Nature Communications, Год журнала: 2023, Номер 14(1)

Опубликована: Фев. 23, 2023

Abstract Diffuse midline glioma-H3K27M mutant (DMG) and glioblastoma (GBM) are the most lethal brain tumors that primarily occur in pediatric adult patients, respectively. Both exhibit significant heterogeneity, shaped by distinct genetic/epigenetic drivers, transcriptional programs including RNA splicing, microenvironmental cues glioma niches. However, spatial organization of cellular states niche-specific regulatory remain to be investigated. Here, we perform a profiling DMG GBM combining short- long-read transcriptomics, single-cell transcriptomic datasets. We identify clinically relevant programs, isoform diversity, multi-cellular ecosystems across different find while tumor core enriches for oligodendrocyte precursor-like cells, radial glial stem-like (RG-like) cells enriched neuron-rich invasive niche both GBM. Further, RG-like functionally confirm FAM20C mediates growth microenvironment human neural stem cell derived orthotopic model. Together, our results provide blueprint understanding architecture vulnerabilities

Язык: Английский

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Integrative spatial analysis reveals a multi-layered organization of glioblastoma

Cell, Год журнала: 2024, Номер 187(10), С. 2485 - 2501.e26

Опубликована: Апрель 22, 2024

Glioma contains malignant cells in diverse states. Here, we combine spatial transcriptomics, proteomics, and computational approaches to define glioma cellular states uncover their organization. We find three prominent modes of First, gliomas are composed small local environments, each typically enriched with one major state. Second, specific pairs preferentially reside proximity across multiple scales. This pairing is consistent tumors. Third, these pairwise interactions collectively a global architecture five layers. Hypoxia appears drive the layers, as it associated long-range organization that includes all cancer cell Accordingly, tumor regions distant from any hypoxic/necrotic foci tumors lack hypoxia such low-grade IDH-mutant less organized. In summary, provide conceptual framework for glioma, highlighting tissue organizer.

Язык: Английский

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Harmonized single-cell landscape, intercellular crosstalk and tumor architecture of glioblastoma

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2022, Номер unknown

Опубликована: Авг. 27, 2022

SUMMARY Glioblastoma, isocitrate dehydrogenase (IDH)-wildtype (hereafter, GB), is an aggressive brain malignancy associated with a dismal prognosis and poor quality of life. Single-cell RNA sequencing has helped to grasp the complexity cell states dynamic changes in GB. Large-scale data integration can help uncover unexplored tumor pathobiology. Here, we resolved composition milieu created cellular map GB (‘GBmap’), curated resource that harmonizes 26 datasets gathering 240 patients spanning over 1.1 million cells. We showcase applications our for reference mapping, transfer learning, biological discoveries. Our results sources pro-angiogenic signaling multifaceted role mesenchymal-like cancer Reconstructing architecture using spatially transcriptomics unveiled high level well-structured neoplastic niches. The GBmap represents framework allows streamlined interpretation new provides platform exploratory analysis, hypothesis generation testing.

Язык: Английский

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Glioblastoma heterogeneity at single cell resolution

Oncogene, Год журнала: 2023, Номер 42(27), С. 2155 - 2165

Опубликована: Июнь 5, 2023

Язык: Английский

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Glioblastoma evolution and heterogeneity from a 3D whole-tumor perspective

Cell, Год журнала: 2024, Номер 187(2), С. 446 - 463.e16

Опубликована: Янв. 1, 2024

Язык: Английский

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Decoding the tumor microenvironment with spatial technologies

Nature Immunology, Год журнала: 2023, Номер 24(12), С. 1982 - 1993

Опубликована: Ноя. 27, 2023

Язык: Английский

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Spatial cellular architecture predicts prognosis in glioblastoma

Nature Communications, Год журнала: 2023, Номер 14(1)

Опубликована: Июль 11, 2023

Abstract Intra-tumoral heterogeneity and cell-state plasticity are key drivers for the therapeutic resistance of glioblastoma. Here, we investigate association between spatial cellular organization glioblastoma prognosis. Leveraging single-cell RNA-seq transcriptomics data, develop a deep learning model to predict transcriptional subtypes cells from histology images. Employing this model, phenotypically analyze 40 million tissue spots 410 patients identify consistent associations tumor architecture prognosis across two independent cohorts. Patients with poor exhibit higher proportions expressing hypoxia-induced program. Furthermore, clustering pattern astrocyte-like is associated worse prognosis, while dispersion connection astrocytes other correlate decreased risk. To validate these results, separate that utilizes images Applying data reveal survival-associated regional gene expression programs. Overall, our study presents scalable approach unravel establishes critical clinical outcomes.

Язык: Английский

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Recent Developments in Glioblastoma Therapy: Oncolytic Viruses and Emerging Future Strategies

Viruses, Год журнала: 2023, Номер 15(2), С. 547 - 547

Опубликована: Фев. 16, 2023

Glioblastoma is the most aggressive form of malignant brain tumor. Standard treatment protocols and traditional immunotherapy are poorly effective as they do not significantly increase long-term survival glioblastoma patients. Oncolytic viruses (OVs) may be an alternative approach. Combining OVs with some modern options also provide significant benefits for Here we review virotherapy glioblastomas describe several their combination other therapies. The personalized use would become a area research aiming to develop regimens glioblastomas.

Язык: Английский

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Emerging role of artificial intelligence in diagnosis, classification and clinical management of glioma

Seminars in Cancer Biology, Год журнала: 2023, Номер 91, С. 110 - 123

Опубликована: Март 11, 2023

Язык: Английский

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Identification of hypoxic macrophages in glioblastoma with therapeutic potential for vasculature normalization

Cancer Cell, Год журнала: 2024, Номер 42(5), С. 815 - 832.e12

Опубликована: Апрель 18, 2024

Monocyte-derived tumor-associated macrophages (Mo-TAMs) intensively infiltrate diffuse gliomas with remarkable heterogeneity. Using single-cell transcriptomics, we chart a spatially resolved transcriptional landscape of Mo-TAMs across 51 patients isocitrate dehydrogenase (IDH)-wild-type glioblastomas or IDH-mutant gliomas. We characterize Mo-TAM subset that is localized to the peri-necrotic niche and skewed by hypoxic cues acquire hypoxia response signature. Hypoxia-TAM destabilizes endothelial adherens junctions activating adrenomedullin paracrine signaling, thereby stimulating hyperpermeable neovasculature hampers drug delivery in glioblastoma xenografts. Accordingly, genetic ablation pharmacological blockade produced restores vascular integrity, improves intratumoral concentration anti-tumor agent dabrafenib, achieves combinatorial therapeutic benefits. Increased proportion expression predictive tumor vessel hyperpermeability worse prognosis glioblastoma. Our findings highlight diversity spatial niche-steered reprogramming indicate potential therapeutics targeting normalize vasculature.

Язык: Английский

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