Spatially resolved multi-omics deciphers bidirectional tumor-host interdependence in glioblastoma

Cancer Cell, Год журнала: 2022, Номер 40(6), С. 639 - 655.e13

Опубликована: Июнь 1, 2022

Glioblastomas are malignant tumors of the central nervous system hallmarked by subclonal diversity and dynamic adaptation amid developmental hierarchies. The source reorganization within spatial context these remains elusive. Here, we characterized glioblastomas spatially resolved transcriptomics, metabolomics, proteomics. By deciphering regionally shared transcriptional programs across patients, infer that glioblastoma is organized segregation lineage states adapts to inflammatory and/or metabolic stimuli, reminiscent reactive transformation in mature astrocytes. Integration imaging mass cytometry uncovered locoregional tumor-host interdependence, resulting exclusive adaptive programs. Inferring copy-number alterations emphasizes a cohesive organization subclones associated with programs, confirming environmental stress gives rise selection pressure. A model stem cells implanted into human rodent neocortical tissue mimicking various environments confirmed originate from environments.

Язык: Английский

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Glioma progression is shaped by genetic evolution and microenvironment interactions

Cell, Год журнала: 2022, Номер 185(12), С. 2184 - 2199.e16

Опубликована: Май 31, 2022

Язык: Английский

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Applications of single-cell RNA sequencing in drug discovery and development

Nature Reviews Drug Discovery, Год журнала: 2023, Номер 22(6), С. 496 - 520

Опубликована: Апрель 28, 2023

Single-cell technologies, particularly single-cell RNA sequencing (scRNA-seq) methods, together with associated computational tools and the growing availability of public data resources, are transforming drug discovery development. New opportunities emerging in target identification owing to improved disease understanding through cell subtyping, highly multiplexed functional genomics screens incorporating scRNA-seq enhancing credentialling prioritization. ScRNA-seq is also aiding selection relevant preclinical models providing new insights into mechanisms action. In clinical development, can inform decision-making via biomarker for patient stratification more precise monitoring response progression. Here, we illustrate how methods being applied key steps discuss ongoing challenges their implementation pharmaceutical industry. There have been significant recent advances development remarkable Ferran colleagues primarily pipeline, from decision-making. Ongoing potential future directions discussed.

Язык: Английский

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Single-cell RNA sequencing reveals evolution of immune landscape during glioblastoma progression

Nature Immunology, Год журнала: 2022, Номер 23(6), С. 971 - 984

Опубликована: Май 27, 2022

Abstract Glioblastoma (GBM) is an incurable primary malignant brain cancer hallmarked with a substantial protumorigenic immune component. Knowledge of the GBM microenvironment during tumor evolution and standard care treatments limited. Using single-cell transcriptomics flow cytometry, we unveiled large-scale comprehensive longitudinal changes in cell composition throughout progression epidermal growth factor receptor-driven genetic mouse model. We identified subsets proinflammatory microglia developing GBMs anti-inflammatory macrophages myeloid-derived suppressors cells end-stage tumors, that parallels breakdown blood–brain barrier extensive receptor + cells. A similar relationship was found between patient biopsies low-grade glioma GBM. Temozolomide decreased accumulation suppressor cells, whereas concomitant temozolomide irradiation increased intratumoral GranzymeB CD8 T but also CD4 regulatory These results provide unbiased cellular landscape its evolutionary progression.

Язык: Английский

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Cancer cell heterogeneity and plasticity: A paradigm shift in glioblastoma

Neuro-Oncology, Год журнала: 2021, Номер 24(5), С. 669 - 682

Опубликована: Ноя. 23, 2021

Phenotypic plasticity has emerged as a major contributor to intra-tumoral heterogeneity and treatment resistance in cancer. Increasing evidence shows that glioblastoma (GBM) cells display prominent intrinsic reversibly adapt dynamic microenvironmental conditions. Limited genetic evolution at recurrence further suggests mechanisms also largely operate the phenotypic level. Here we review recent literature underpinning role of GBM creating gradients heterogeneous including those carry cancer stem cell (CSC) properties. A historical perspective from hierarchical nonhierarchical concept CSCs towards appreciation is provided. Cellular states interact dynamically with each other surrounding brain shape flexible tumor ecosystem, which enables swift adaptation external pressure treatment. We present key components regulating equilibrium states, genetic, epigenetic, factors. discuss context resistance, where variable balance between preexisting resistant adaptive persisters leads reversible upon Innovative efforts targeting regulators state transitions treatment-resistant are needed restrict capacities GBM.

Язык: Английский

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Challenges in glioblastoma research: focus on the tumor microenvironment

Trends in cancer, Год журнала: 2022, Номер 9(1), С. 9 - 27

Опубликована: Ноя. 16, 2022

Язык: Английский

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Hypoxic niches attract and sequester tumor-associated macrophages and cytotoxic T cells and reprogram them for immunosuppression

Immunity, Год журнала: 2023, Номер 56(8), С. 1825 - 1843.e6

Опубликована: Июль 13, 2023

Язык: Английский

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Live-Cell Imaging Shows Uneven Segregation of Extrachromosomal DNA Elements and Transcriptionally Active Extrachromosomal DNA Hubs in Cancer

Cancer Discovery, Год журнала: 2021, Номер 12(2), С. 468 - 483

Опубликована: Ноя. 24, 2021

Oncogenic extrachromosomal DNA elements (ecDNA) play an important role in tumor evolution, but our understanding of ecDNA biology is limited. We determined the distribution single-cell copy number across patient tissues and cell line models observed how cell-to-cell frequency varies greatly. The exceptional intratumoral heterogeneity suggested ecDNA-specific replication propagation mechanisms. To evaluate transfer genetic material from parental to offspring cells during mitosis, we established CRISPR-based ecTag method. leverages breakpoint sequences tag with fluorescent markers living cells. Applying mitosis revealed disjointed inheritance patterns, enabling rapid accumulation individual After ecDNAs clustered into hubs, hubs colocalized RNA polymerase II, promoting transcription cargo oncogenes. Our observations provide direct evidence for uneven segregation shed new light on mechanisms through which contribute oncogenesis. SIGNIFICANCE: are vehicles oncogene amplification. circular nature affords unique properties, such as mobility behavior. uncovered fundamental properties by tracking live cells, highlighting random that drive gene transcription.See related commentary Henssen, p. 293.This article highlighted In This Issue feature, 275.

Язык: Английский

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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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Interrogating glioma-M2 macrophage interactions identifies Gal-9/Tim-3 as a viable target against PTEN -null glioblastoma

Science Advances, Год журнала: 2022, Номер 8(27)

Опубликована: Июль 8, 2022

Genomic alteration can reshape tumor microenvironment to drive malignancy. However, how PTEN deficiency influences microenvironment-mediated cell-cell interactions in glioblastoma (GBM) remains unclear. Here, we show that induces a symbiotic glioma-M2 macrophage interaction support glioma progression. Mechanistically, -deficient GBM cells secrete high levels of galectin-9 (Gal-9) via the AKT-GSK3β-IRF1 pathway. The secreted Gal-9 drives M2 polarization by activating its receptor Tim-3 and downstream pathways macrophages. These macrophages, turn, VEGFA stimulate angiogenesis growth. Furthermore, enhanced Gal-9/Tim-3 expression predicts poor outcome patients. In models, blockade signaling inhibits suppresses Moreover, α-lactose attenuates down-regulating macrophage-derived VEGFA, providing novel antivascularization strategy. Therefore, our study suggests is effective impair progression inhibiting polarization, specifically for -null GBM.

Язык: Английский

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