Spitzer Avishay, Johnson Kevin C, Nomura Masashi, Garofano Luciano, Nehar-Belaid Djamel, Darnell Noam Galili, Greenwald Alissa C, Bussema Lillian, Oh Young Taek, Varn Frederick S, D'Angelo Fulvio, Gritsch Simon, Anderson Kevin J, Migliozzi Simona, Gonzalez Castro L Nicolas, Chowdhury Tamrin, Robine Nicolas, Reeves Catherine, Park Jong Bae, Lipsa Anuja, Hertel Frank, Golebiewska Anna, Niclou Simone P, Nusrat Labeeba, Kellet Sorcha, Das Sunit, Moon Hyo-Eun, Paek Sun Ha, Bielle Franck, Laurenge Alice, Di Stefano Anna Luisa, Mathon Bertrand, Picca Alberto, Sanson Marc, Tanaka Shota, Saito Nobuhito, Ashley David M, Keir Stephen T, Ligon Keith L, Huse Jason T, Yung W K Alfred, Lasorella Anna, Iavarone Antonio, Verhaak Roel G W, Tirosh Itay, Suvà Mario L
Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel.
Department of Oncology, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel.
Nat Genet. 2025 May;57(5):1168-1178. doi: 10.1038/s41588-025-02168-4. Epub 2025 May 9.
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.
异柠檬酸脱氢酶（IDH）野生型胶质母细胞瘤（GBM）在标准治疗后的演变仍知之甚少。在此，我们使用单核RNA测序和大量DNA测序分析了59例患者配对的原发性和复发性GBM，评估了GBM生态系统在细胞和分子异质性层面的纵向演变。最一致的变化是复发时恶性细胞比例降低，肿瘤微环境（TME）中神经胶质细胞和神经元细胞类型相应增加。大多数配对之间主要的恶性细胞状态不同，但在任一时刻点都没有特定状态是唯一的或高度富集的，并且在整个队列中也没有一致的纵向轨迹。然而，特定轨迹在部分患者亚组中富集。恶性状态丰度的变化反映了TME组成和基线特征的变化，体现了GBM生态系统的共同进化。我们的研究提供了GBM多样纵向轨迹的蓝图，并突出了塑造这些轨迹的治疗和TME调节因子。
