ArticleNature genetics2025
The multilayered transcriptional architecture of glioblastoma ecosystems.
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Article in Nature genetics, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 79 papers.
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79citing papers in PubMed
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Who cites it
79 citing papers in PubMed.
- Identification of CD74-Positive Antigen-Presenting Glioma Cells in Primary Human Tumors and Murine Models of NF1 High-Grade Glioma.Molecular cancer therapeutics · 2026Article
- Accelerating discovery: Transformative clinical trial models in neuro-oncology.Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics · 2026Review
- Review
- Gliomas phenocopy an inborn error of metabolism to drive neuronal activity and tumor growth.Cell · 2026Article
- Glioblastoma recurrence: An NGS-centered seed-soil framework.Neoplasia (New York, N.Y.) · 2026Article
- Multi-sampling allows intra-tumoral heterogeneity querying and vulnerability profiling in glioblastoma.Neuro-oncology · 2026Article
- Decoding WDR5-Mediated Interactions in Gliomas: Implications for Targeted Therapy.Medicinal research reviews · 2026Review
- Clinical and molecular features of primary gliosarcoma with digital spatial whole-transcriptome analysis of glial and mesenchymal components.Brain pathology (Zurich, Switzerland) · 2026Article
- FAPExperimental & molecular medicine · 2026Article
- Flash Assembloids: A Rapid Biofabrication of a Platform for Modeling Early Glioblastoma Invasion at the Glioblastoma-Brain Organoid Interfaces.Advanced healthcare materials · 2026Article
- Integrating Radiogenomics and CSF-Based Liquid Biopsy Sequencing for Precision Neuro-Oncology.International journal of molecular sciences · 2026Review
- The Invasive Margin of Glioblastoma as a Molecular Ecosystem: Spatial Heterogeneity, Tumor-Host Interactions, and Therapeutic Opportunities.International journal of molecular sciences · 2026Review
- Brain barriers at the crossroads of glioma immune surveillance and immunotherapy response.Nature reviews. Cancer · 2026Review
- Charting intratumor heterogeneity from bench to bedside.Nature cancer · 2026Review
- Identifying a Csmd3Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- Spatial Omics Technologies in Glioblastoma Research: Principles, Applications, and Best Practices.Genes · 2026Review
- Integrated PANoptosis Profiling Identifies Immunosuppressive Subtypes and a Prognostic Signature With Functional Validation of MLKL in Glioblastoma.Annals of clinical and translational neurology · 2026Article
- Longitudinal changes in DNA methylation in IDH-mutant glioma fuel disease progression through altered cell state differentiation.Nature genetics · 2026Article
- Article
- Optic nerve sheath meningioma exhibits neural niche-associated transcriptomic features and rare copy number variation-linked evolution.Brain pathology (Zurich, Switzerland) · 2026Article
19 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
46 authors.
Masashi Nomura *Department of Pathology and Krantz Family Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.ORCID http://orcid.org/0000-0001-6095-7849
Avishay Spitzer *Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel.
Kevin C Johnson *Department of Neurosurgery, Yale School of Medicine, New Haven, CT, USA.ORCID http://orcid.org/0000-0003-0016-5158
Luciano Garofano *Department of Public Health Sciences, Division of Biostatistics and Bioinformatics, University of Miami, Miller School of Medicine, Miami, FL, USA.ORCID http://orcid.org/0000-0001-8582-0865
Djamel Nehar-BelaidThe Jackson Laboratory for Genomic Medicine, Farmington, CT, USA.ORCID http://orcid.org/0000-0001-6002-5021
Noam Galili DarnellDepartment of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel.ORCID http://orcid.org/0009-0008-7624-0250
Alissa C GreenwaldDepartment of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel.
Lillian BussemaDepartment of Pathology and Krantz Family Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.ORCID http://orcid.org/0000-0001-5469-3816
Young Taek OhSylvester Comprehensive Cancer Center, University of Miami, Miller School of Medicine, Miami, FL, USA.
Frederick S VarnThe Jackson Laboratory for Genomic Medicine, Farmington, CT, USA.ORCID http://orcid.org/0000-0001-6307-016X
Fulvio D'AngeloSylvester Comprehensive Cancer Center, University of Miami, Miller School of Medicine, Miami, FL, USA.ORCID http://orcid.org/0000-0002-4940-4693
Simon GritschDepartment of Pathology and Krantz Family Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
Kevin J AndersonThe Jackson Laboratory for Genomic Medicine, Farmington, CT, USA.ORCID http://orcid.org/0000-0002-2362-273X
Simona MigliozziSylvester Comprehensive Cancer Center, University of Miami, Miller School of Medicine, Miami, FL, USA.
L Nicolas Gonzalez CastroDepartment of Pathology and Krantz Family Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.ORCID http://orcid.org/0000-0001-7699-5188
Tamrin ChowdhFuryDepartment of Neurosurgery, Yale School of Medicine, New Haven, CT, USA.
Nicolas RobineDepartment of Computational Biology, New York Genome Center, New York, NY, USA.ORCID http://orcid.org/0000-0001-5698-8183
Catherine ReevesDepartment of Sequencing Operations, New York Genome Center, New York, NY, USA.ORCID http://orcid.org/0000-0002-9942-8909
Jong Bae ParkDepartment of Cancer Biomedical Science, Graduate School of Cancer Science and Policy, National Cancer Center, Goyang, Republic of Korea.ORCID http://orcid.org/0000-0003-0207-0697
Anuja LipsaNORLUX Neuro-Oncology laboratory, Department of Cancer Research, Luxembourg Institute of Health, Luxembourg, Luxembourg.ORCID http://orcid.org/0000-0002-9668-6048
Frank HertelNORLUX Neuro-Oncology laboratory, Department of Cancer Research, Luxembourg Institute of Health, Luxembourg, Luxembourg.
Anna GolebiewskaNORLUX Neuro-Oncology laboratory, Department of Cancer Research, Luxembourg Institute of Health, Luxembourg, Luxembourg.ORCID http://orcid.org/0000-0002-4160-2521
Simone P NiclouNORLUX Neuro-Oncology laboratory, Department of Cancer Research, Luxembourg Institute of Health, Luxembourg, Luxembourg.ORCID http://orcid.org/0000-0002-3417-9534
Labeeba NusratDivision of Neurosurgery, St. Michael's Hospital, University of Toronto, Toronto, Ontario, Canada.
Sorcha KelletDivision of Neurosurgery, St. Michael's Hospital, University of Toronto, Toronto, Ontario, Canada.
Sunit DasDivision of Neurosurgery, St. Michael's Hospital, University of Toronto, Toronto, Ontario, Canada.
Hyo Eun MoonDepartment of Neurosurgery, Cancer Research Institute, Hypoxia Ischemia Disease Institute, Seoul National University, Seoul, Republic of Korea.
Sun Ha PaekDepartment of Neurosurgery, Cancer Research Institute, Hypoxia Ischemia Disease Institute, Seoul National University, Seoul, Republic of Korea.ORCID http://orcid.org/0000-0003-3007-8653
Franck BielleSorbonne Université, UMR S 1127, Inserm U 1127, CNRS UMR 7225, ICM-Paris Brain Institute, Equipe Labellisée LNCC, Paris, France.ORCID http://orcid.org/0000-0001-6564-6388
Alice LaurengeSorbonne Université, UMR S 1127, Inserm U 1127, CNRS UMR 7225, ICM-Paris Brain Institute, Equipe Labellisée LNCC, Paris, France.ORCID http://orcid.org/0000-0002-0058-3176
Anna Luisa Di StefanoNeurology Department, Foch Hospital, Suresnes, France.ORCID http://orcid.org/0000-0003-1746-0647
Bertrand MathonAP-HP, Groupe Hospitalier Pitié-Salpêtrière, Neurosurgery, Paris, France.ORCID http://orcid.org/0000-0002-9182-5846
Alberto PiccaSorbonne Université, UMR S 1127, Inserm U 1127, CNRS UMR 7225, ICM-Paris Brain Institute, Equipe Labellisée LNCC, Paris, France.
Marc SansonSorbonne Université, UMR S 1127, Inserm U 1127, CNRS UMR 7225, ICM-Paris Brain Institute, Equipe Labellisée LNCC, Paris, France.
Shota TanakaDepartment of Neurosurgery, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
Nobuhito SaitoDepartment of Neurosurgery, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
David M AshleyDepartment of Neurosurgery, The Preston Robert Tisch Brain Tumor Center, Duke University, Durham, NC, USA.ORCID http://orcid.org/0000-0002-4754-5900
Stephen T KeirDepartment of Neurosurgery, The Preston Robert Tisch Brain Tumor Center, Duke University, Durham, NC, USA.
Keith L LigonDepartment of Pathology, Brigham and Women's Hospital, Boston, MA, USA.ORCID http://orcid.org/0000-0002-7733-600X
Jason T HuseDepartment of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.ORCID http://orcid.org/0000-0003-4514-0640
W K Alfred YungDepartment of Neuro-Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.ORCID http://orcid.org/0000-0002-1669-0793
Anna LasorellaSylvester Comprehensive Cancer Center, University of Miami, Miller School of Medicine, Miami, FL, USA. axl4252@med.miami.edu.ORCID http://orcid.org/0000-0002-1839-5421
Roel G W VerhaakDepartment of Neurosurgery, Yale School of Medicine, New Haven, CT, USA. roel.verhaak@yale.edu.ORCID http://orcid.org/0000-0003-2773-0436
Antonio IavaroneSylvester Comprehensive Cancer Center, University of Miami, Miller School of Medicine, Miami, FL, USA. axi435@med.miami.edu.ORCID http://orcid.org/0000-0002-0683-4634
Mario L SuvàDepartment of Pathology and Krantz Family Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA. Suva.Mario@mgh.harvard.edu.ORCID http://orcid.org/0000-0001-9898-5351
Itay TiroshDepartment of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel. Itayt@weizmann.ac.il.ORCID http://orcid.org/0000-0001-5477-2987
Funding
VectorP30CA006516 · NCI · DANA-FARBER CANCER INSTITUTE · PI Irene M. Ghobrial · 1985 to 2026
$330.6MTumor Biology and Microenvironment ProgramP30CA013696 · NCI · COLUMBIA UNIV NEW YORK MORNINGSIDE · PI Anil K Rustgi · 1985 to 2026
$115.3MShared Resource ManagementP30CA034196 · NCI · JACKSON LABORATORY · PI Paul Robson · 1985 to 2026
$61.9MTargeting the Vasular SystemP50CA165962 · NCI · MASSACHUSETTS GENERAL HOSPITAL · PI Tracy T Batchelor · 2013 to 2026
$33.5MTumor Biology Research ProgramP30CA240139 · NCI · UNIVERSITY OF MIAMI SCHOOL OF MEDICINE · PI Stephen D. Nimer · 2019 to 2026
$24.1MOncogenic mechanisms, molecular stratification and therapeutic targets of brain tumorsR35CA253183 · NCI · UNIVERSITY OF MIAMI SCHOOL OF MEDICINE · PI Antonio Iavarone · 2021 to 2026
$5.2MDissecting the cellular hierarchies of malignant gliomas by single-cell functional genomicsR37CA245523 · NCI · MASSACHUSETTS GENERAL HOSPITAL · PI Mario Luca Suva · 2020 to 2026
$2.8MDeciphering heritability, plasticity and differentiation trajectories in gliomas via single-cell multi-omicsR01CA258763 · NCI · MASSACHUSETTS GENERAL HOSPITAL · PI SUVA, MARIO LUCA · 2021 to 2025
$2.8MDissecting the Determinants of IDH-mutant Gliomas Response to Mutant IDH InhibitorsR01CA276765 · NCI · MASSACHUSETTS GENERAL HOSPITAL · PI Daniel P. Cahill, Mario Luca Suva · 2023 to 2026
$2.7MExtrachromosomal DNA as a Targetable Mechanism in GlioblastomaR01CA237208 · NCI · YALE UNIVERSITY · PI VERHAAK, ROEL GW · 2020 to 2024
$2.5MEvolution and targeting of the functional states of glioblastomaR01CA268592 · NCI · UNIVERSITY OF MIAMI SCHOOL OF MEDICINE · PI Antonio Iavarone, ANNA LASORELLA · 2022 to 2026
$2.0MMechanisms of ID2 regulation in gliomaR01CA239721 · NCI · UNIVERSITY OF MIAMI SCHOOL OF MEDICINE · PI LASORELLA, ANNA · 2019 to 2023
$1.8MNCI NIH HHS P30 CA006516NCI NIH HHS P30 CA013696NCI NIH HHS P30 CA034196NCI NIH HHS P30 CA240139NCI NIH HHS P50 CA165962NCI NIH HHS R01 CA237208NCI NIH HHS R01 CA239721NCI NIH HHS R01 CA258763NCI NIH HHS R01 CA268592NCI NIH HHS R01 CA276765NCI NIH HHS R01 CA280560NCI NIH HHS R21 CA256575NCI NIH HHS R35 CA253183NCI NIH HHS R37 CA245523NINDS NIH HHS R21 NS114873
Abstract
In isocitrate dehydrogenase wildtype glioblastoma (GBM), cellular heterogeneity across and within tumors may drive therapeutic resistance. Here we analyzed 121 primary and recurrent GBM samples from 59 patients using single-nucleus RNA sequencing and bulk tumor DNA sequencing to characterize GBM transcriptional heterogeneity. First, GBMs can be classified by their broad cellular composition, encompassing malignant and nonmalignant cell types. Second, in each cell type we describe the diversity of cellular states and their pathway activation, particularly an expanded set of malignant cell states, including glial progenitor cell-like, neuronal-like and cilia-like. Third, the remaining variation between GBMs highlights three baseline gene expression programs. These three layers of heterogeneity are interrelated and partially associated with specific genetic aberrations, thereby defining three stereotypic GBM ecosystems. This work provides an unparalleled view of the multilayered transcriptional architecture of GBM. How this architecture evolves during disease progression is addressed in the companion manuscript by Spitzer et al.
Indexed as
Brain NeoplasmsGlioblastomaTranscription, GeneticGene Expression ProfilingGene Expression Regulation, NeoplasticHumansIsocitrate DehydrogenaseTranscriptomeIsocitrate Dehydrogenase
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