Acquired genetic and cell-state changes in IDH-mutant glioma progression

• 成果类型: Article
• 署名作者: Johnson, Kevin C.; Spitzer, Avishay; Varn, Frederick S.; Nomura, Masashi; Garofano, Luciano; Chowdhury, Tamrin; Lipsa, Anuja; Zhang, Linbin; Fernandez, Ester Calvo; Barak, Tanyeri; Gulhan Ercan-Sencicek, A.; Peksen, Ayse Buket; Anderson, Kevin J.; Tesileanu, C. Mircea S.; Amin, Samirkumar B.; Kocakavuk, Emre; Zhao, Dacheng; D'Angelo, Fulvio; Migliozzi, Simona; Bussema, Lillian; Gritsch, Simon; Moon, Hyo-Eun; Paek, Sun Ha; Bielle, Franck; Laurenge, Alice; Di Stefano, Anna Luisa; Mathon, Bertrand; Picca, Alberto; Sanson, Marc; Hau, Ann-Christin; Hertel, Frank; Grzyb, Kamil; Zhao, Zheng; Wang, Qianghu; Jiang, Tao; Miller, Julie J.; Wakimoto, Hiroaki; Cahill, Daniel P.; Moliterno, Jennifer; Gunel, Murat; Hermes, Beth; Sanai, Nader; Golebiewska, Anna; Niclou, Simone P.; Huse, Jason; Alfred Yung, W. K.; Lasorella, Anna; Suva, Mario L.; Iavarone, Antonio; Tirosh, Itay; Verhaak, Roel G. W.
• 署名单位: Yale University; Weizmann Institute of Science; Tel Aviv University; Sackler Faculty of Medicine; Tel Aviv Sourasky Medical Center; Jackson Laboratory; University of Connecticut; University of Connecticut; Harvard University; Harvard University Medical Affiliates; Massachusetts General Hospital; Harvard University; Harvard Medical School; Harvard University; Massachusetts Institute of Technology (MIT); Broad Institute; University of Tokyo; Harvard University; Harvard University Medical Affiliates; Massachusetts General Hospital; University of Miami; University of Miami; Luxembourg Institute of Health; University of Duisburg Essen; University of Miami; University of Miami; Seoul National University (SNU); Seoul National University (SNU); Sorbonne Universite; Centre National de la Recherche Scientifique (CNRS); Institut National de la Sante et de la Recherche Medicale (Inserm); Sorbonne Universite; Assistance Publique Hopitaux Paris (APHP); Hopital Universitaire Pitie-Salpetriere - APHP; Sorbonne Universite; Assistance Publique Hopitaux Paris (APHP); Hopital Universitaire Pitie-Salpetriere - APHP; Hospital Foch; Sorbonne Universite; Assistance Publique Hopitaux Paris (APHP); Hopital Universitaire Pitie-Salpetriere - APHP; Beijing Neurosurgical Institute; Capital Medical University; Nanjing Medical University; Nanjing Medical University; Harvard University; Harvard Medical School; Harvard University Medical Affiliates; Massachusetts General Hospital; Harvard University; Harvard Medical School; Harvard University Medical Affiliates; Massachusetts General Hospital; Harvard University; Harvard Medical School; Harvard University Medical Affiliates; Massachusetts General Hospital; St. Joseph's Hospital and Medical Center; Barrow Neurological Institute; Barrow Neurological Institute; University of Texas System; UTMD Anderson Cancer Center; University of Texas System; UTMD Anderson Cancer Center; University of Amsterdam; Translational Genomics Research Institute
• 刊物名称: NATURE
• ISSN/ISSBN: 0028-0836; 1476-4687
• DOI: 10.1038/s41586-026-10612-6
• 发表日期: 2026-07-23
• 关键词: single-cell; rna-seq; reveals; EVOLUTION; landscape; tumors; stem

摘要

Gliomas with mutant isocitrate dehydrogenase (IDH) are malignant brain tumours that typically arise in early to mid-adulthood and nearly always recur following treatment1,2. However, the genetic and cellular-state changes that drive IDH-mutant glioma progression under treatment remain incompletely understood. Here we integrated single-nucleus transcriptomic profiles, chromatin accessibility profiles and bulk DNA and RNA sequencing from 75 temporally separated gliomas across 35 patients comprising both the oligodendroglioma and astrocytoma IDH-mutant glioma tumour types. We show that malignant cell states transcriptionally resemble stages of normal glial-neuronal lineage development or a reactive mesenchymal-like state, mirroring states previously described in IDH wild-type glioblastoma3,4. Malignant cell states displayed distinct chromatin accessibility profiles that were comparable between both IDH-mutant glioma types. The abundance of less differentiated malignant cells increased with grade and with genetic alterations such as PDGFRA amplification. Longitudinal analysis highlighted two major malignant cell-state transition patterns. First, reduced lineage differentiation and increased proliferative malignant cells at recurrence were enriched in gliomas that acquired recurrence-associated genetic events. These included treatment-associated hypermutation, increased copy number changes and cell cycle alterations. Second, increased mesenchymal-like-state abundance occurred independently of acquired genetic alterations and instead coincided with elevated macrophage expression. Overall, our findings provide an integrative model that traces the cell intrinsic and extrinsic factors that shape cellular states during IDH-mutant glioma disease progression.