bims-malgli 2026-09-20 papers

bims-malgli

Biomed News

on Biology of malignant gliomas

Issue of 2026–09–20
ten papers selected by
Oltea Sampetrean, Keio University

The Spatiotemporal Evolution of Radiation Resistance in Glioblastoma.
Scherer's map, remapped.
Spatial analysis reveals the evolving organization of IDH-mutant glioma.
Levetiracetam therapeutically targets GABAergic synapses in diffuse midline glioma.
Autophagy inhibition sensitizes radiotherapy responses in high-grade mutant IDH1 glioma.
Murine modeling of IDH-mutant 1p/19q-codeleted oligodendroglioma reveals genotype specific phenotypes.
Immune Cell Engager Therapy for Brain Cancer.
Gliomas phenocopy an inborn error of metabolism to drive neuronal activity and tumor growth.
Integrated 3D light sheet and 2D multiplex imaging for deep histological characterization of somatic mouse glioblastoma.
Tunneling nanotubes regulate mitochondrial homeostasis between glioblastoma and astrocytes, and between tumor cells in vivo.

Neuro Oncol. 2026 Sep 15. pii: noag209. [Epub ahead of print]

The Spatiotemporal Evolution of Radiation Resistance in Glioblastoma.

Lingxiang Wu, Lei Cheng, Bin Huang, Runheng Huang, Ravesanker Ezhilarasan, Junxia Zhang, Wei Wu, Guojing Wu, Benqing Yu, Lindsey D Goodman, Ananya Jambhale, Baoli Hu, Apeng Chen, Mengyan Zhu, Min Wu, Peng Xia, Quanzhong Liu, Miao Yu, Zheng Zhao, Zhangchun Cheng, Ning Wang, Fan Lin, Fengqi Zhou, Ze-Yan Zhang, Yingwen Ding, Jian Chen, Xu Qian, Xiuxing Wang, Yu Shi, Joy Gumin, Krishna Bhat, W K Alfred Yung, Kenneth D Aldape, Roel G W Verhaak, Frederick F Lang, Yongping You, Jiankai Yang, Qianghu Wang, Erik P Sulman.

   BACKGROUND: Although radiation therapy (RT) remains one of the most effective treatments for patients with the lethal brain tumor glioblastoma (GBM), quite a number of patients show resistance or relapse shortly after RT. There is an urgent need to uncover the temporal and spatial dynamics of RT resistance during tumor progression and treatment.
METHODS: The radio-resistance signature score (RRSS) was calculated by utilizing glioma sphere-forming cells (GSCs) which recapitulate the transcriptomic landscape of GBM.
RESULTS: RRSS can assess the RT response on both cell lines and GBM patients. Both transdifferentiated and irradiated glioma cells show increased radiation resistance, demonstrating that the recurrent GBM may acquire resistance along with cell differentiation and selective advantage during treatment. Moreover, RRSS of the marginal tumors is found to be higher than that of core tumors (Wilcoxon's rank-sum test, p-value<0.01). The infiltration of macrophages was significantly associated with radiation resistance (p-value<0.01), which was further validated by single-cell RNAseq based experiments and clonogenic assays. Moreover, we demonstrated that IL1B, a pro-inflammatory cytokine secreted by macrophages, could enhance the radiation resistance of tumor cells.
CONCLUSIONS: Our study revealed the spatiotemporal evolution of radiation resistance of GBM, and shed light on the development of novel adjuvant therapeutic strategies.

Keywords:  glioblastoma; glioma sphere-forming cells; radiotherapy resistance; tumor evolution

DOI:  https://doi.org/10.1093/neuonc/noag209
Cancer Cell. 2026 Sep 14. pii: S1535-6108(26)00358-2. [Epub ahead of print]44(9): 1730-1732

Scherer's map, remapped.

Daniel J Silver, Chang Xu, Justin D Lathia.

Scherer's century-old classification of expansive and infiltrative glioma growth remains foundational to neuro-oncology. In this issue of Cancer Cell, Hoefflin et al. use spatial RNA and protein profiling of IDH-mutant gliomas to reveal hypoxia and necrosis as organizing centers of expansive growth and white-matter tracts as guides and constraints on invasion.

DOI: https://doi.org/10.1016/j.ccell.2026.08.002
Cancer Cell. 2026 Sep 14. pii: S1535-6108(26)00382-X. [Epub ahead of print]44(9): 1882-1892.e7

Spatial analysis reveals the evolving organization of IDH-mutant glioma.

Rouven Hoefflin, Alissa C Greenwald, Noam Galili Darnell, Christopher W Mount, Yali Tiomkin, L Nicolas Gonzalez Castro, Zebin Wen, Dor Simkin, Angelica B Patterson, Inna Goliand, Ofra Golani, Liat Fellus-Alyagor, Marina Cohen, Kevin Joseph, Jürgen Beck, Vidhya M Ravi, Merav Kedmi, Hadas Keren-Shaul, Michael Weller, Yoseph Addadi, Marian C Neidert, Mario L Suvà, Itay Tirosh.

  Adult diffuse gliomas are composed of malignant cell states interwoven with the non-malignant brain microenvironment. Here, we combine spatial transcriptomics and spatial proteomics of isocitrate dehydrogenase (IDH)-mutant gliomas to define organizational principles across histological grades. In low-grade tumors, spatial organization is shaped by underlying brain anatomy. We identify a functional white-gray matter junction that restricts cortical invasion and is associated with marked changes in tumor composition and cellular phenotypes. This junction is preferentially traversed by oligodendrocyte progenitor (OPC)-like malignant cells, suggesting a role in tumor expansion. In contrast, tumors with intermediate histological features are largely disorganized, with few recurring interactions between cancer cell states and microenvironmental cell types. In high-grade tumors, hypoxia-associated structure emerges, resembling IDH-wild-type glioblastoma. Together, these findings reveal two independent axes of spatial organization-from anatomy-driven structure in low-grade tumors to hypoxia-driven organization in high-grade tumors-and establish a framework linking tumor grade to recurrent spatial interactions.

Keywords:  IDH-mutant glioma; spatial omics; spatial organization; tumor invasion; tumor microenvironment

DOI:  https://doi.org/10.1016/j.ccell.2026.08.005
Nat Med. 2026 Sep 17.

Levetiracetam therapeutically targets GABAergic synapses in diffuse midline glioma.

Tara Barron, Richard Drexler, Aaron Mochizuki, Evan Cantor, Kiarash Shamardani, Pamelyn J Woo, Neeraj Soni, Dana Tlais, Andrea Franson, Samantha Lyons, Truman Knowles, Shannon Raber, Vilina Mehta, Michael A Quezada, Michael B Keough, Samin Malaki Jahan, Linh Thuy Vo, Enrique Herrera Castañeda, Kathryn R Taylor, Lijun Ni, Kim Kilian, Samuel H Wu, Franz L Ricklefs, Ulrich Schüller, Sabine Mueller, Paul G Fisher, Cynthia J Campen, Hannes Vogel, Sonia Partap, Kai Kaila, Carl Koschmann, Michelle Monje.

Antiseizure medications, such as levetiracetam, are commonly used in glioma patients. Retrospective analyses evaluating effects of antiseizure medications on glioma patient survival have yielded inconsistent results, probably due to confounding factors of glioma subtype and drug class. Here we present retrospective real-world clinical data that demonstrate longer overall survival for children with diffuse midline glioma (DMG) who were taking levetiracetam, which was not evident in pediatric patients with hemispheric high-grade glioma. In preclinical models, levetiracetam reduces glioma proliferation and tumor burden, extending survival of mice bearing DMG orthotopic xenografts. These beneficial effects were not found in hemispheric high-grade glioma patient-derived orthotopic xenograft models. The subtype-specificity of this antiproliferative effect of levetiracetam is congruent with recent findings that GABAergic neuron-to-glioma synapses promote glioma growth in DMG but not hemispheric high-grade glioma. We demonstrate here that levetiracetam attenuates low-frequency GABAergic synaptic transmission in a glioma-specific manner, reducing GABAergic synaptic currents in DMG but not in healthy neurons. This effect is independent of action on SV2A, the chief mechanism by which levetiracetam functions to prevent and treat seizures. Taken together, these findings indicate a promising approach to target GABAergic synapses in DMG and suggest that use of levetiracetam in DMG should be further studied in future prospective clinical studies.

DOI: https://doi.org/10.1038/s41591-026-04646-6
Nat Commun. 2026 Sep 18. pii: 9740. [Epub ahead of print]17(1):

Autophagy inhibition sensitizes radiotherapy responses in high-grade mutant IDH1 glioma.

Felipe J Núñez, Kaushik Banerjee, Anzar A Mujeeb, Ava Mauser, Claire E Tronrud, Ziwen Zhu, Sadhakshi Raghuram, Maya R Sheth, Jorge Armando Pena Agudelo, Julio Zelaya, Ayman Taher, Padma Kadiyala, Stephen V Carney, Maria B Garcia-Fabiani, Andrea Comba, Mahmoud S Alghamri, Brandon L McClellan, Adam Klaiss, Zeribe C Nwosu, Hanna S Hong, Peter Sajjakulnukit, Tingting Qin, Maureen A Sartor, Mats Ljungman, Joshua D Welch, Shi-Yuan Cheng, Pedro R Lowenstein, Joerg Lahann, Costas A Lyssiotis, Maria G Castro.

Mutant isocitrate dehydrogenase 1 (mIDH1) catalyzes 2-hydroxyglutarate (2HG) production which leads to epigenetic reprogramming in astrocytomas with tumor protein p53 (TP53)/α-thalassemia/mental retardation, X-linked (ATRX) loss. RNA-sequencing, single-cell RNA-sequencing, and Chromatin Immunoprecipitation sequencing (ChIP-seq) followed by bioinformatics analysis shows that human and mouse mIDH1 gliomas exhibit downregulated gene ontologies (GOs) related to mitochondrial metabolism and upregulated autophagy-related GOs. Decreased mitochondrial metabolism is accompanied by decreased glycolysis, rendering autophagy as a source of energy in mIDH1 gliomas. Mutant IDH1 glioma cells exhibit increased expression of autophagy-related proteins and enhanced microtubule-associated protein 1 light chain 3 (LC3) I/II conversion, indicating augmented autophagy. Inhibiting autophagy in vivo by administration of synthetic protein nanoparticles (SPNPs) encapsulating autophagy related gene 7 (ATG7) silencing RNA sensitizes mIDH1 glioma cells to radiation, resulting in tumor regression, long-term survival, and immunological memory. This work uncovers autophagy as a critical pathway for survival in mIDH1 gliomas and its inhibition elicits radiosensitivity in vitro in human and mouse mIDH1 glioma cells, and in vivo in mIDH1 models.

DOI: https://doi.org/10.1038/s41467-026-77320-7
Neuro Oncol. 2026 Sep 17. pii: noag228. [Epub ahead of print]

Murine modeling of IDH-mutant 1p/19q-codeleted oligodendroglioma reveals genotype specific phenotypes.

Ipsita G Kundu, Nicolas Toro, Aaron Y Mochizuki, Jaldeep Langhnoja, Rithvik V Ayyagari, James C Cronk, Sarah M Reel, Phonepasong Arounleut, Luis E Tron Esqueda, Christine E Fuller, Pavithra Viswanath, Amy B Heimberger, Craig M Horbinski, Timothy N Phoenix.

   BACKGROUND: Oligodendroglioma is a primary central nervous system tumor classified by the presence of isocitrate dehydrogenase (IDH) mutations and codeletion of 1p/19q. A lack of faithful preclinical model systems for this disease has limited progress in understanding the biology of this genetically unique subtype of adult diffuse-type glioma and in developing new effective therapies. To address this unmet need, we sought to establish a mouse model that faithfully recapitulates the genetic and phenotypic features of human IDH-mutant 1p/19q-codeleted oligodendroglioma.
METHODS: We performed in utero electroporation to introduce distinct combinations of genetic alterations and evaluated their potential to form tumors. Resulting tumors were characterized by histology, metabolite profiling, RNA-sequencing and single-cell RNA sequencing.
RESULTS: We identified co-expression of IDH1R132H and PIK3CAE545K together with loss of Cic, Fubp1 and Cdkn2a (termed OligoCdkn2a) as the optimal genetic combination to drive fully penetrant tumors that histologically resemble human grade II/III IDH-mutant 1p/19q-codeleted oligodendroglioma. Substituting Cdkn2a loss with Trp53 deletion decreased latency and shifted tumors toward high-grade astrocytoma histology. OligoCdkn2a tumors displayed metabolic and transcriptional changes associated with IDH and CIC mutations, and single-cell sequencing identified a bias towards oligodendrocyte differentiation compared to an IDH wild-type glioblastoma mouse model.
CONCLUSIONS: To our knowledge, OligoCdkn2a tumors represent the first autochthonous, genetically engineered mouse model to recapitulate the genetic, histological and transcriptional features of human IDH-mutant 1p/19q-codeleted oligodendrogliomas. This model will provide a valuable platform to further dissect mechanisms of tumorigenesis and test novel therapeutic strategies for this molecularly distinct glioma subtype.

Keywords:  1p/19q-codeletion; IDH mutation; In-utero electroporation; Mouse models; Oligodendroglioma

DOI:  https://doi.org/10.1093/neuonc/noag228
Neuro Oncol. 2026 Sep 18. pii: noag227. [Epub ahead of print]

Immune Cell Engager Therapy for Brain Cancer.

Daan A Sluijter, Rianne van Garderen, Ilse van Haveren, Jan Meeldijk, Sandra Crnko, Thijs Koorman, Toine Ten Broeke, Michael Y Schakelaar, Niels Bovenschen.

  Improving outcomes for patients with brain tumors remains a formidable challenge. Patient survival is often considered very poor even though standard first line treatments include surgery, radiotherapy, and chemotherapy. These therapies often have detrimental side effects on brain functions and do not suffice when tumors advance and metastasize, prompting the need for new treatment modalities. Recent innovations in antibody-based immunotherapies may complement brain cancer treatment. Biotechnical engineering platforms yield new antibody-inspired biomolecules for optimal engagement of specific and tumor-associated antigens, which also recruit and elicit immune effector cell functions. Here, we review current advances on multi-specific immune cell engagers for brain tumor treatment and provide novel insights into overcoming existing challenges.

Keywords:  Brain cancer; Immune cell engager; TriKE; TriTE

DOI:  https://doi.org/10.1093/neuonc/noag227
Cell. 2026 Sep 15. pii: S0092-8674(26)01010-X. [Epub ahead of print]

Gliomas phenocopy an inborn error of metabolism to drive neuronal activity and tumor growth.

Kalil G Abdullah, Kenji Miki, Charles K Edgar, Shuangcheng Alivia Wu, Yi Xiao, Yuan-Tai Huang, Richard Drexler, Saritha Krishna, Vinesh T Puliyappadamba, Li Wei Rachel Tay, Fanen Yuan, Milan R Savani, Maged T Ghoche, Shawn E Kotermanski, Jeffrey I Traylor, Lei Guo, Kathryn Gunn, William H Hicks, Diana D Shi, Belgin Yalçın, Kim Kilian, Min Tang, Mitchell Moyer, Michael M Levitt, Mohamad El-Shami, Skyler Oken, Namya Manoj, Lauren C Gattie, Bailey C Smith, Pranita Kaphle, Tracey Shipman, Raymond E West, Chaoying Liang, Yasmina Eshac, Tzu-Yi Chia, Toral R Patel, Kimmo J Hatanpaa, Prithvi Raj, Jason M Miska, Denise M O Ramirez, Shang Ma, Thomas D Nolin, Bradley C Lega, Pascal O Zinn, Bianca J Kuhn, Natalie M Clark, C Williams, D R Mani, Michael A Gillette, Marco A Calzado, Lin Xu, Lauren G Zacharias, Feng Cai, Alexander Ksendzovsky, Thomas P Mathews, Julie-Aurore Losman, Benjamin Levi, Tara Barron, Jay R Gibson, Timothy E Richardson, Osaama H Khan, Sameer Agnihotri, Shawn L Hervey-Jumper, Simon Chamberland, Michelle Monje, Kimberly M Huber, Ralph J DeBerardinis, Samuel K McBrayer.

  The metabolic hallmarks of high-grade glioma (HGG) are not fully understood. Human brain tissue metabolomics revealed that the creatine synthesis pathway intermediate guanidinoacetate (GAA) accumulated ∼100-fold in HGGs relative to controls, which was caused by imbalanced activities of enzymes in this pathway. Glioma cells secreted GAA rather than using it to produce creatine, implicating an alternative function. GAA accumulates in GAA N-methyltransferase (GAMT) deficiency, an inborn error of metabolism, and elevates neuronal excitability. Neuronal excitability is also increased in glioma and drives tumor growth through neuron-glioma interactions. We hypothesized that glioma-generated GAA excites surrounding neurons. Indeed, GAA induced neuronal hyperactivity by activating GABAA receptors and causing depolarizing currents in glioma-associated neurons with dysregulated chloride homeostasis. Depleting tumoral GAA decreased electrochemical activity, neuron-glioma interactions, and tumor aggressiveness. Our findings unveil a mechanism linking cancer metabolism with cancer neuroscience and leverage human genetics to nominate GAA synthesis as a target in gliomas.

Keywords:  GABA; GAMT deficiency; cancer metabolism; cancer neuroscience; creatine; glioma; guanidinoacetate; inborn error of metabolism; metabolite signaling

DOI:  https://doi.org/10.1016/j.cell.2026.08.037
iScience. 2026 Sep 18. 29(9): 117476

Integrated 3D light sheet and 2D multiplex imaging for deep histological characterization of somatic mouse glioblastoma.

Marie Catherine Tiveron, Nathalie Coré, Kevin Bigott, Yliana Huriaux Fontana, Maria Caccavale, Léna Vilvandre, Fabio El Yassouri, Victoria Schoppel, Silvia Rüberg, Melanie Jungblut, Dominique Figarella-Branger, Aurélie Tchoghandjian, Andreas Bosio, Harold Cremer.

  Glioblastoma is a devastating brain cancer for which patient survival has remained largely unchanged for decades, underscoring the need for improved disease modeling and analytical tools. Neural stem cells have been identified as cells of origin of glioblastoma, leading to the development of somatic lineage models. Such models have been deeply characterized by sequencing but systematic histological analyses remain limited. Here, we present a multimodal histological characterization of a somatic glioblastoma mouse model. Using 3D light-sheet imaging, we show that the model is highly reproducible and enables quantitative assessment of tumor growth across cohorts. Through multiplex imaging with MACSima™ Imaging Cyclic Staining, we map the cellular landscape and molecular architecture of the tumors and their environments, and provide a curated resource of mouse-compatible antibodies. Finally, we demonstrate that tissue clearing and light-sheet microscopy can be seamlessly combined with multiplex imaging, enabling spatial proteomic characterization of a 3D pre-defined tumor.

Keywords:  brain electroporation; light sheet imaging; multiplex imaging; neural stem cells; somatic glioblastoma model

DOI:  https://doi.org/10.1016/j.isci.2026.117476
Nat Commun. 2026 09 15. pii: 9788. [Epub ahead of print]17(1):

Tunneling nanotubes regulate mitochondrial homeostasis between glioblastoma and astrocytes, and between tumor cells in vivo.

Ines Saenz-de-Santa-Maria, Anna Pepe, Jean-Yves Tinevez, Christel Brou, Yakov Vitrenko, Thomas Cokelaer, Elizabeth Cohen-Jonathan Moyal, Roberto Weigert, Chiara Zurzolo.

Tumor progression is driven by cancer cells' ability to establish a cellular network through tunneling nanotube-like connections (TNTs), which enable mitochondrial exchange both within the tumor cells and with the tumor microenvironment (TME). However, the functional consequences of mitochondrial transfer between tumor and non-tumor cells, and its occurrence in vivo, remain poorly understood. Here we show bidirectional mitochondrial transfer between Glioblastoma (GBM) cells and non-tumoral astrocytes (AS). We report that transfer of damaged mitochondria from GBM cells to AS is associated with activation of mitophagy in recipient cells, while astrocyte-derived mitochondria to GBM cells correlates with changes in mitochondrial activity and metabolic readouts. Furthermore, intravital subcellular microscopy (ISMic) in a live animal model allows the visualization of TNT connections with characteristics similar to those observed in vitro and supported TNT-mediated mitochondrial transfer in vivo. These findings reveal a potential mechanism of tumor adaptation and highlight TNTs as promising therapeutic targets.

DOI: https://doi.org/10.1038/s41467-026-76619-9