OS05.2.A DECIPHERING THE LONGITUDINAL TRAJECTORIES OF GLIOBLASTOMA ECOSYSTEMS BY INTEGRATIVE SINGLE-CELL GENOMICS

Abstract BACKGROUND The mechanisms governing the progression of IDH-wildtype glioblastoma (GBM) following standard-of-care therapy remain incompletely understood. While recurrence is nearly universal, the cellular and molecular trajectories that underpin this process - particularly the dynamics of tumor and microenvironmental compartments - have yet to be fully resolved. MATERIAL AND METHODS To dissect the longitudinal evolution of the GBM ecosystem, we analyzed paired primary and recurrent tumor specimens from 59 patients. We employed single-nucleus RNA sequencing to profile transcriptomic states at single-cell resolution and integrated these data with bulk DNA sequencing to assess genomic alterations. This approach enabled a comprehensive interrogation of cellular heterogeneity and malignant state transitions over time. RESULTS Across the cohort, the most consistent feature at recurrence was a decreased proportion of malignant cells, accompanied by a reciprocal expansion of non-malignant glial and neuronal cell populations within the tumor microenvironment (TME). While the dominant malignant cell state often differed between primary and recurrent samples, no state was uniquely associated with a specific disease stage. Moreover, no singular evolutionary trajectory characterized the cohort as a whole. Instead, subsets of patients exhibited enriched and partially convergent state transitions. Notably, shifts in malignant cell states were mirrored by concurrent remodeling of the TME, implicating a tightly interwoven pattern of tumor-microenvironment co-evolution. CONCLUSION These findings reveal diverse and patient-specific evolutionary trajectories in IDH-wildtype GBM, shaped by both therapeutic pressure and microenvironmental context. Our study provides a reference framework for understanding longitudinal GBM dynamics and highlights the importance of ecosystem-level interactions in driving recurrence.

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Publication Details

Journal
Neuro-Oncology
Published
2025-10-01
DOI
https://doi.org/10.1093/neuonc/noaf193.050
Primary Topic
Single-cell and spatial transcriptomics
Type
article
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article

OS05.2.A DECIPHERING THE LONGITUDINAL TRAJECTORIES OF GLIOBLASTOMA ECOSYSTEMS BY INTEGRATIVE SINGLE-CELL GENOMICS

Itay Tirosh, Keith Lloyd Ligon, Mario L. Suvà, Luciano Garofano et al.
Neuro-Oncology
Single-cell and spatial transcriptomics
article

OS05.2.A DECIPHERING THE LONGITUDINAL TRAJECTORIES OF GLIOBLASTOMA ECOSYSTEMS BY INTEGRATIVE SINGLE-CELL GENOMICS

Itay Tirosh, Keith Lloyd Ligon, Mario L. Suvà, Luciano Garofano, Masashi Nomura, Frederick S. Varn, L Gonzalez Castro, S Paek, Nicolas Robine, Stephen T. Keir, S Gritsch, Djamel Nehar-Belaid, Alice Laurenge, Anna Golebiewska, Anthony G. Greenwald, S Migliozzi, Kevin J. Anderson, Franck Bielle, Roel G.W. Verhaak, Sunit Das, Nobuhito Saito, Hyeong‐Gon Moon, Simone P. Niclou, J. T. Huse, Alan R. Spitzer, Anna Lasorella, David M. Ashley, Kevin C. Johnson, Jongsun Park, Labeeba Nusrat, A Lipsa, Marc Sanson, Yeonyee Oh, Tamrin Chowdhury, Bertrand Mathon, Lillian Bussema, Antonio Iavarone, Anna Luisa Di Stefano, Shigenori Tanaka, Salomey Kellett, Alberto Pïcca, Catherine Reeves, Noam Galili Darnell, Francesca D’Angelo, Frank Hertel, W.K. Alfred Yung
article en

Abstract

Abstract BACKGROUND The mechanisms governing the progression of IDH-wildtype glioblastoma (GBM) following standard-of-care therapy remain incompletely understood. While recurrence is nearly universal, the cellular and molecular trajectories that underpin this process - particularly the dynamics of tumor and microenvironmental compartments - have yet to be fully resolved. MATERIAL AND METHODS To dissect the longitudinal evolution of the GBM ecosystem, we analyzed paired primary and recurrent tumor specimens from 59 patients. We employed single-nucleus RNA sequencing to profile transcriptomic states at single-cell resolution and integrated these data with bulk DNA sequencing to assess genomic alterations. This approach enabled a comprehensive interrogation of cellular heterogeneity and malignant state transitions over time. RESULTS Across the cohort, the most consistent feature at recurrence was a decreased proportion of malignant cells, accompanied by a reciprocal expansion of non-malignant glial and neuronal cell populations within the tumor microenvironment (TME). While the dominant malignant cell state often differed between primary and recurrent samples, no state was uniquely associated with a specific disease stage. Moreover, no singular evolutionary trajectory characterized the cohort as a whole. Instead, subsets of patients exhibited enriched and partially convergent state transitions. Notably, shifts in malignant cell states were mirrored by concurrent remodeling of the TME, implicating a tightly interwoven pattern of tumor-microenvironment co-evolution. CONCLUSION These findings reveal diverse and patient-specific evolutionary trajectories in IDH-wildtype GBM, shaped by both therapeutic pressure and microenvironmental context. Our study provides a reference framework for understanding longitudinal GBM dynamics and highlights the importance of ecosystem-level interactions in driving recurrence.

Neuro-OncologyVol. 27(Supplement_3)
Broad Institute (US), Brigham and Women's Hospital (US), St. Michael's Hospital (CA), Allen Institute for Brain Science (US), The University of Texas MD Anderson Cancer Center (US), Harvard University (US), Seoul National University (KR), University of Connecticut (US), University of Miami (US), Tel Aviv University (IL), Duke University (US), University of Toronto (CA), Tel Aviv Sourasky Medical Center (IL), Yale University (US), Sorbonne Université (FR), Massachusetts General Hospital (US), National Cancer Center (US), Assistance Publique – Hôpitaux de Paris (FR), Luxembourg Institute of Health (LU), American Committee for the Weizmann Institute of Science (US), Institut de Myologie (FR), Jackson Laboratory (US), Dana-Farber Cancer Institute (US), National Cancer Center (KR), Pitié-Salpêtrière Hospital (FR), Ospedale di Livorno (IT), Center for Cancer Research (US), New York Genome Center (US), Amsterdam University Medical Centers (NL), Pediatric Brain Tumor Foundation (US), Sylvester Comprehensive Cancer Center (US), Neurological Surgery (US), Weizmann Institute of Science (IL), The University of Tokyo (JP), UConn Health (US), University of Amsterdam (NL)
Openalex Percentile: Top 76%
Single-cell and spatial transcriptomics
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