EPCO-34. DECIPHERING THE LONGITUDINAL TRAJECTORIES OF GLIOBLASTOMA BY INTEGRATIVE SINGLE-CELL GENOMICS

Abstract The evolution of cellular heterogeneity in IDH-wildtype glioblastoma (GBM) after standard-of-care therapy remains poorly understood. To address it, we assembled a longitudinal cohort of 121 primary and recurrent GBM specimens from 59 patients, with extensive clinical annotations, and profiled it by single-nucleus RNA-sequencing and bulk tumor DNA sequencing. In most cases, longitudinal samples diverged in their composition of cell types and cell states. However, almost all theoretical trajectories were observed in our cohort such that the overall distribution of cell types and cell states was comparable between primary and recurrent samples. The most consistent longitudinal effect (66% of patients) was a lower malignant cell fraction at recurrence and a reciprocal increase in proportions of glio-neuronal TME cell types; in some cases, this was further accompanied by a coordinated shift of malignant cells towards neuronal-like states. MGMT methylation and radiation-related small deletion phenotypes were linked to particular trajectories, with depletion of mesenchymal-like cells and enrichment of hypoxia-related malignant cells, respectively. Importantly, changes in malignant states were also associated with specific changes in TME composition. In summary, our analysis highlights diverse longitudinal GBM trajectories that are shaped by treatment response and TME interactions.

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Publication Details

Journal
Neuro-Oncology
Published
2024-11-01
DOI
https://doi.org/10.1093/neuonc/noae165.0033
Primary Topic
Single-cell and spatial transcriptomics
Type
article
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article

EPCO-34. DECIPHERING THE LONGITUDINAL TRAJECTORIES OF GLIOBLASTOMA BY INTEGRATIVE SINGLE-CELL GENOMICS

Shota Tanaka, Itay Tirosh, Simona Migliozzi, L. Nicolas Gonzalez Castro et al.
Neuro-Oncology
Single-cell and spatial transcriptomics
article

EPCO-34. DECIPHERING THE LONGITUDINAL TRAJECTORIES OF GLIOBLASTOMA BY INTEGRATIVE SINGLE-CELL GENOMICS

Shota Tanaka, Itay Tirosh, Simona Migliozzi, L. Nicolas Gonzalez Castro, Anuja Lipsa, Alissa Greenwald, Mario L. Suvà, Luciano Garofano, Frederick S. Varn, Jason T. Huse, Nicolas Robine, Fulvio D’Angelo, Stephen T. Keir, Djamel Nehar-Belaid, Hyo-Eun Moon, Alice Laurenge, Avishay Spitzer, Anna Golebiewska, Kevin J. Anderson, Franck Bielle, Roel G.W. Verhaak, Sunit Das, Nobuhito Saito, Simone P. Niclou, Anna Lasorella, Sun Ha Paek, David M. Ashley, Kevin C. Johnson, Young Taek Oh, Simon Gritsch, Labeeba Nusrat, Marc Sanson, Tamrin Chowdhury, Bertrand Mathon, Lillian Bussema, Antonio Iavarone, Alberto Pïcca, Catherine Reeves, Noam Galili Darnell, Jong Bae Park, Frank Hertel, Masashi Nomura, Anna Luisa Di Stefano, W. K. Alfred Yung, Sorcha Kellet
article en

Abstract

Abstract The evolution of cellular heterogeneity in IDH-wildtype glioblastoma (GBM) after standard-of-care therapy remains poorly understood. To address it, we assembled a longitudinal cohort of 121 primary and recurrent GBM specimens from 59 patients, with extensive clinical annotations, and profiled it by single-nucleus RNA-sequencing and bulk tumor DNA sequencing. In most cases, longitudinal samples diverged in their composition of cell types and cell states. However, almost all theoretical trajectories were observed in our cohort such that the overall distribution of cell types and cell states was comparable between primary and recurrent samples. The most consistent longitudinal effect (66% of patients) was a lower malignant cell fraction at recurrence and a reciprocal increase in proportions of glio-neuronal TME cell types; in some cases, this was further accompanied by a coordinated shift of malignant cells towards neuronal-like states. MGMT methylation and radiation-related small deletion phenotypes were linked to particular trajectories, with depletion of mesenchymal-like cells and enrichment of hypoxia-related malignant cells, respectively. Importantly, changes in malignant states were also associated with specific changes in TME composition. In summary, our analysis highlights diverse longitudinal GBM trajectories that are shaped by treatment response and TME interactions.

Neuro-OncologyVol. 26(Supplement_8)
Broad Institute (US), St. Michael's Hospital (CA), The University of Texas MD Anderson Cancer Center (US), Harvard University (US), Seoul National University (KR), University of Miami (US), Duke University (US), University of Toronto (CA), Tel Aviv Sourasky Medical Center (IL), Yale University (US), Sorbonne Université (FR), Massachusetts General Hospital (US), Assistance Publique – Hôpitaux de Paris (FR), Luxembourg Institute of Health (LU), Jackson Laboratory (US), National Cancer Center (KR), Advanced Institute of Convergence Technology (KR), Pitié-Salpêtrière Hospital (FR), Ospedale di Livorno (IT), Center for Cancer Research (US), New York Genome Center (US), Hôpital Foch (FR), Sylvester Comprehensive Cancer Center (US), Neurological Surgery (US), Weizmann Institute of Science (IL), The University of Tokyo (JP), UConn Health (US)
Good health and well-being
Openalex Percentile: Top 82%
Single-cell and spatial transcriptomics
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