Multi-omics characterization of IDH-mutant astrocytoma-derived cell lines reveals NOTCH-regulated plastic quiescent astrocyte-like state and insights into progression
9 affiliations
- 1IGF, Univ Montpellier, CNRS, Inserm
- 2Inserm, CEA, Stabilité Génétique Cellules Souches Et Radiations, LRP/iRCM/IBFJ, Université Paris Cité
- 3Université de Montpellier
- 4Institut de Recherche en Cancérologie (IRCM), INSERM
- 5BCM, CNRS, INSERM, Université Montpellier
- 6AP-HP, Institut du Cerveau (ICM), CNRS, INSERM, Hôpitaux Universitaires La Pitié Salpêtrière - Charles Foix, Service de Neuro-Oncologie-Institut de Neurologie, Sorbonne Université
- 7School of Biological and Health Systems Engineering, Arizona State University
- 8Department of Neurosurgery, Xinqiao Hospital, Third Military Medical University (Army Medical University)
- 9Jinfeng Laboratory
Abstract
Diffuse IDH-mutant astrocytomas are brain tumors typically diagnosed as low-grade but capable of progressing to higher grades. They exhibit three cellular states resembling astrocytes, oligodendrocytes, and neural progenitor (NPC) cells. Understanding their biology has been limited by the scarcity of relevant in vitro models. Here, we established and extensively characterized four astrocytoma cell lines (LGG275, LGG336, LGG85, LGG349) derived from IDH-mutant astrocytomas of different grades and analyzed them using multi-omics approaches. These lines display growth rates in vitro and in vivo consistent with tumor grade and recapitulate some key molecular alterations observed in patient tumors, including IDH1, ATRX, and TP53 mutations, ALT (alternative lengthening of telomeres) activation and, in more aggressive lines, MET and PDGFRA alterations. Single-cell RNA sequencing revealed three major transcriptional states (astrocyte-like, oligodendrocyte-like, and NPC-like), consistent with those described in patient tumors. A hallmark of higher-grade-derived lines (LGG85, LGG349) is the persistence of NPC-like populations without growth factors possibly reflecting tumor progression. The LGG275 line most accurately mirrors slow-growing astrocytomas. Using CD44 and GLAST, we isolated astrocyte-like (CD44⁺/GLAST⁺) cells from LGG275 that preferentially adopt a quiescent state yet retain remarkable plasticity, generating oligodendrocyte-like cells (CD44⁻/GLAST⁻). Transcriptomic and proteomic analyses revealed that astrocyte-like and oligodendrocyte-like cells populations resemble, respectively, quiescent and activated neural stem (NSC) cells from the adult subventricular zone (SVZ). Finally, we provide evidence that NOTCH signaling contributes to the regulation of cell state balance, promoting transitions toward an astrocyte-like transcriptional program while DLL3, an anti-Notch protein, expressed by oligodendrocyte-like cells, modulates both proliferation and phenotype. These cell lines represent valuable resources for dissecting lineage dynamics, heterogeneity, and progression mechanisms in IDH-mutant astrocytomas. Graphical abstract
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BibTeX
@article{garcia2026multiomics,
title = {{Multi-omics characterization of IDH-mutant astrocytoma-derived cell lines reveals NOTCH-regulated plastic quiescent astrocyte-like state and insights into progression}},
author = {Leonor Garcia and Christine Granotier-Beckers and Donovan Pineau and Dassou Sika and Szimonetta Hideg and Camille Labadie and Kasandra Aguilar Cázarez and Jigna Kundnani and Lucille Stuani and Laurent R. Gauthier and François D. Boussin and Marc-André Mouthon and Serge Urbach and Khadija El Koulali and Martial Séveno and Chantal Ripoll and Kawtar Daddi and Maité Verreault and Ahmed Idbaih and Samantha O’Connor and Christopher L. Plaisier and Wei Chen and Sheng-Qing Lv and Lei Zhang and Min Zheng and Valérie Rigau and Hugues Duffau and Jean-Philippe Hugnot},
journal = {Acta Neuropathologica Communications},
year = {2026},
month = jul,
doi = {10.1186/s40478-026-02316-9},
url = {https://doi.org/10.1186/s40478-026-02316-9},
note = {CC BY},
}
RIS
TY - JOUR
TI - Multi-omics characterization of IDH-mutant astrocytoma-derived cell lines reveals NOTCH-regulated plastic quiescent astrocyte-like state and insights into progression
AU - Leonor Garcia
AU - Christine Granotier-Beckers
AU - Donovan Pineau
AU - Dassou Sika
AU - Szimonetta Hideg
AU - Camille Labadie
AU - Kasandra Aguilar Cázarez
AU - Jigna Kundnani
AU - Lucille Stuani
AU - Laurent R. Gauthier
AU - François D. Boussin
AU - Marc-André Mouthon
AU - Serge Urbach
AU - Khadija El Koulali
AU - Martial Séveno
AU - Chantal Ripoll
AU - Kawtar Daddi
AU - Maité Verreault
AU - Ahmed Idbaih
AU - Samantha O’Connor
AU - Christopher L. Plaisier
AU - Wei Chen
AU - Sheng-Qing Lv
AU - Lei Zhang
AU - Min Zheng
AU - Valérie Rigau
AU - Hugues Duffau
AU - Jean-Philippe Hugnot
PY - 2026
DA - 2026/07/01
JO - Acta Neuropathologica Communications
DO - 10.1186/s40478-026-02316-9
UR - https://doi.org/10.1186/s40478-026-02316-9
AB - Diffuse IDH-mutant astrocytomas are brain tumors typically diagnosed as low-grade but capable of progressing to higher grades. They exhibit three cellular states resembling astrocytes, oligodendrocytes, and neural progenitor (NPC) cells. Understanding their biology has been limited by the scarcity of relevant in vitro models. Here, we established and extensively characterized four astrocytoma cell lines (LGG275, LGG336, LGG85, LGG349) derived from IDH-mutant astrocytomas of different grades and analyzed them using multi-omics approaches. These lines display growth rates in vitro and in vivo consistent with tumor grade and recapitulate some key molecular alterations observed in patient tumors, including IDH1, ATRX, and TP53 mutations, ALT (alternative lengthening of telomeres) activation and, in more aggressive lines, MET and PDGFRA alterations. Single-cell RNA sequencing revealed three major transcriptional states (astrocyte-like, oligodendrocyte-like, and NPC-like), consistent with those described in patient tumors. A hallmark of higher-grade-derived lines (LGG85, LGG349) is the persistence of NPC-like populations without growth factors possibly reflecting tumor progression. The LGG275 line most accurately mirrors slow-growing astrocytomas. Using CD44 and GLAST, we isolated astrocyte-like (CD44⁺/GLAST⁺) cells from LGG275 that preferentially adopt a quiescent state yet retain remarkable plasticity, generating oligodendrocyte-like cells (CD44⁻/GLAST⁻). Transcriptomic and proteomic analyses revealed that astrocyte-like and oligodendrocyte-like cells populations resemble, respectively, quiescent and activated neural stem (NSC) cells from the adult subventricular zone (SVZ). Finally, we provide evidence that NOTCH signaling contributes to the regulation of cell state balance, promoting transitions toward an astrocyte-like transcriptional program while DLL3, an anti-Notch protein, expressed by oligodendrocyte-like cells, modulates both proliferation and phenotype. These cell lines represent valuable resources for dissecting lineage dynamics, heterogeneity, and progression mechanisms in IDH-mutant astrocytomas. Graphical abstract
SN - 2051-5960
ER -