Single‐cell RNA sequencing reveals tumor heterogeneity, microenvironment, and drug‐resistance mechanisms of recurrent glioblastoma DOI Creative Commons
Haibin Wu, Chengcheng Guo, Chaoye Wang

et al.

Cancer Science, Journal Year: 2023, Volume and Issue: 114(6), P. 2609 - 2621

Published: Feb. 28, 2023

Glioblastomas are highly heterogeneous brain tumors. Despite the availability of standard treatment for glioblastoma multiforme (GBM), i.e., Stupp protocol, which involves surgical resection followed by radiotherapy and chemotherapy, remains refractory to recurrence is inevitable. Moreover, biology recurrent unclear. Increasing evidence has shown that intratumoral heterogeneity tumor microenvironment contribute therapeutic resistance. However, interaction between intracellular drug resistance in GBMs controversial. The aim this study was map transcriptome landscape cancer cells drug-resistant at a single-cell resolution further explore mechanism GBMs. We analyzed six tissue samples from three patients with primary GBM developed after protocol using RNA sequencing. Using unbiased clustering, nine major cell clusters were identified. Upregulation expression stemness-related cell-cycle-related genes observed cells. Compared initial tissues, tissues showed decreased proportion microglia, consistent previous reports. Finally, vascular endothelial growth factor A blood-brain barrier permeability high, O6 -methylguanine DNA methyltransferase-related signaling pathway activated GBM. Our results delineate glioblastoma, heterogeneity, microenvironment, drug-resistance mechanisms, providing new insights into strategies glioblastomas.

Language: Английский

Spatially resolved multi-omics deciphers bidirectional tumor-host interdependence in glioblastoma DOI Creative Commons
Vidhya M. Ravi, Paulina Will,

Jan Kueckelhaus

et al.

Cancer Cell, Journal Year: 2022, Volume and Issue: 40(6), P. 639 - 655.e13

Published: June 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.

Language: Английский

Citations

337
Glioma progression is shaped by genetic evolution and microenvironment interactions DOI Creative Commons
Frederick S. Varn, Kevin C. Johnson, Jan Martínek

et al.

Cell, Journal Year: 2022, Volume and Issue: 185(12), P. 2184 - 2199.e16

Published: May 31, 2022

Language: Английский

Citations

294
Applications of single-cell RNA sequencing in drug discovery and development DOI Creative Commons
Bram Van de Sande, Joon Sang Lee, Euphemia Mutasa-Gottgens

et al.

Nature Reviews Drug Discovery, Journal Year: 2023, Volume and Issue: 22(6), P. 496 - 520

Published: April 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.

Language: Английский

Citations

205
Single-cell RNA sequencing reveals evolution of immune landscape during glioblastoma progression DOI Creative Commons
Alan T. Yeo, Shruti Rawal,

Bethany Delcuze

et al.

Nature Immunology, Journal Year: 2022, Volume and Issue: 23(6), P. 971 - 984

Published: May 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.

Language: Английский

Citations

178
Cancer cell heterogeneity and plasticity: A paradigm shift in glioblastoma DOI Creative Commons
Yahaya A Yabo, Simone P. Niclou, Anna Golebiewska

et al.

Neuro-Oncology, Journal Year: 2021, Volume and Issue: 24(5), P. 669 - 682

Published: Nov. 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.

Language: Английский

Citations

172
Challenges in glioblastoma research: focus on the tumor microenvironment DOI Creative Commons
Andréas Bikfalvi, Cristine Alvès da Costa, Tony Avril

et al.

Trends in cancer, Journal Year: 2022, Volume and Issue: 9(1), P. 9 - 27

Published: Nov. 16, 2022

Language: Английский

Citations

169
Live-Cell Imaging Shows Uneven Segregation of Extrachromosomal DNA Elements and Transcriptionally Active Extrachromosomal DNA Hubs in Cancer DOI Open Access
Eunhee Yi, Amit D. Gujar, Molly Guthrie

et al.

Cancer Discovery, Journal Year: 2021, Volume and Issue: 12(2), P. 468 - 483

Published: Nov. 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.

Language: Английский

Citations

110
Hypoxic niches attract and sequester tumor-associated macrophages and cytotoxic T cells and reprogram them for immunosuppression DOI Creative Commons
Anirudh Sattiraju, Sang Jo Kang, Bruno Giotti

et al.

Immunity, Journal Year: 2023, Volume and Issue: 56(8), P. 1825 - 1843.e6

Published: July 13, 2023

Language: Английский

Citations

110
Spatial transcriptomics reveals niche-specific enrichment and vulnerabilities of radial glial stem-like cells in malignant gliomas DOI Creative Commons
Yanming Ren,

Zongyao Huang,

Lingling Zhou

et al.

Nature Communications, Journal Year: 2023, Volume and Issue: 14(1)

Published: Feb. 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

Language: Английский

Citations

86
Harmonized single-cell landscape, intercellular crosstalk and tumor architecture of glioblastoma DOI Creative Commons
Cristian Ruiz-Moreno, Sergio Marco Salas, Erik Samuelsson

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2022, Volume and Issue: unknown

Published: Aug. 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.

Language: Английский

Citations

84