ArticleNature genetics2025
Deciphering the longitudinal trajectories of glioblastoma ecosystems by integrative single-cell genomics.
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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 55 papers.
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55citing papers in PubMed
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Who cites it
55 citing papers in PubMed.
- Brain barriers at the crossroads of glioma immune surveillance and immunotherapy response.Nature reviews. Cancer · 2026Review
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- Pervasive Somatic Mutations inbioRxiv : the preprint server for biology · 2026Article
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- Clinical and molecular features of primary gliosarcoma with digital spatial whole-transcriptome analysis of glial and mesenchymal components.Brain pathology (Zurich, Switzerland) · 2026Article
- The Invasive Margin of Glioblastoma as a Molecular Ecosystem: Spatial Heterogeneity, Tumor-Host Interactions, and Therapeutic Opportunities.International journal of molecular sciences · 2026Review
- Stem-like characteristics across sequentially temozolomide-adapted glioblastoma cell populations with increasing levels of acquired resistance.Molecular biology reports · 2026Article
- Charting intratumor heterogeneity from bench to bedside.Nature cancer · 2026Review
- Article
- Spatial Omics Technologies in Glioblastoma Research: Principles, Applications, and Best Practices.Genes · 2026Review
- Single-cell multi-omic analyses resolve the cellular diversity of ALK/ROS1/MET/NTRK-fused gliomas in infants and older children.bioRxiv : the preprint server for biology · 2026Article
- Article
- Longitudinal changes in DNA methylation in IDH-mutant glioma fuel disease progression through altered cell state differentiation.Nature genetics · 2026Article
- Decoding glioblastoma evolution and heterogeneity through mechanistic modeling: implications for clinical translation.Journal of experimental & clinical cancer research : CR · 2026Review
- Review
- Role of NR2F2-mediated reprogramming of endothelial cells in glioblastoma progression.iScience · 2026Article
- Molecular insights into DNA damage response plasticity in glioma stem cells.Communications biology · 2026Review
- DNA-PKcs inhibition sensitizes glioblastoma to radiotherapy through reprogramming of tumor cell states and immune microenvironment cell types.Research square · 2026Article
- Tumor transcriptional state predicts survival in immune-checkpoint-blockade-treated glioblastoma.Nature cancer · 2026Article
Corrections and comments
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Authors and funding
46 authors.
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
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
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 ChowdhuryDepartment of Neurosurgery, Yale School of Medicine, New Haven, CT, USA.
Nicolas RobineDepartment of Computational Biology, New York Genome Center, New York City, NY, USA.ORCID http://orcid.org/0000-0001-5698-8183
Catherine ReevesDepartment of Sequencing Operations, New York Genome Center, New York City, 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
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
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
Itay TiroshDepartment of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel. Itay.tirosh@weizmann.ac.il.ORCID http://orcid.org/0000-0001-5477-2987
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
Funding
VectorP30CA006516 · NCI · DANA-FARBER CANCER INSTITUTE · PI A. Heather Eliassen · 1985 to 2026
$330.6MTumor Biology and Microenvironment ProgramP30CA013696 · NCI · COLUMBIA UNIV NEW YORK MORNINGSIDE · PI Parisa Tehranifar · 1985 to 2026
$115.3MShared Resource ManagementP30CA034196 · NCI · JACKSON LABORATORY · PI William Carl Skarnes · 1985 to 2026
$61.9MTargeting the Vasular SystemP50CA165962 · NCI · MASSACHUSETTS GENERAL HOSPITAL · PI Benjamin Harris Kann · 2013 to 2026
$33.5MTumor Biology Research ProgramP30CA240139 · NCI · UNIVERSITY OF MIAMI SCHOOL OF MEDICINE · PI Daniel Bilbao · 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
The evolution of isocitrate dehydrogenase (IDH)-wildtype glioblastoma (GBM) after standard-of-care therapy remains poorly understood. Here we analyzed matched primary and recurrent GBMs from 59 patients using single-nucleus RNA sequencing and bulk DNA sequencing, assessing the longitudinal evolution of the GBM ecosystem across layers of cellular and molecular heterogeneity. The most consistent change was a lower malignant cell fraction at recurrence and a reciprocal increase in glial and neuronal cell types in the tumor microenvironment (TME). The predominant malignant cell state differed between most matched pairs, but no states were exclusive or highly enriched in either time point, nor was there a consistent longitudinal trajectory across the cohort. Nevertheless, specific trajectories were enriched in subsets of patients. Changes in malignant state abundances mirrored changes in TME composition and baseline profiles, reflecting the co-evolution of the GBM ecosystem. Our study provides a blueprint of GBM's diverse longitudinal trajectories and highlights the treatment and TME modifiers that shape them.
Indexed as
Brain NeoplasmsGenomicsGlioblastomaSingle-Cell AnalysisTumor MicroenvironmentFemaleHumansIsocitrate DehydrogenaseLongitudinal StudiesMaleMiddle AgedNeoplasm Recurrence, LocalIsocitrate Dehydrogenase
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