bims-malgli Biomed News
on Biology of malignant gliomas
Issue of 2025–08–24
six papers selected by
Oltea Sampetrean, Keio University
  1. Mutant IDH silences GSX2 to reprogram neural progenitor cell fate and promote gliomagenesis.
  2. Membrane flexibility induced by BST2 contributes to radioresistance in glioblastoma.
  3. Bioengineered hybrid dual-targeting nanoparticles reprogram the tumour microenvironment for deep glioblastoma photodynamic therapy.
  4. Systematic decoding of functional enhancer connectomes and risk variants in human glioma.
  5. Revisiting an old therapy for new, promising combinations: biology and perspectives of lomustine in glioma treatment.
  6. Long-range cholinergic input promotes glioblastoma progression.
  1. bioRxiv. 2025 Aug 13. pii: 2025.08.12.667486. [Epub ahead of print]
    Mutant IDH silences GSX2 to reprogram neural progenitor cell fate and promote gliomagenesis.
    Yi Xiao, Diana D Shi, Lei Guo, Ethan Neumann, Michael M Levitt, Pranita Kaphle, Tracey Shipman, Haocheng Li, Feng Cai, Denise M O Ramirez, Lauren G Zacharias, Zhenkang Chen, Mathew Lin, Vinesh T Puliyappadamba, Tao Chen, Milan R Savani, Salvador Peña, Janaka Wansapura, Thomas P Mathews, Prashant Mishra, Yoon Jung Kim, Prithvi Raj, Timothy E Richardson, Jian Xu, Stephen C Mack, Gilbert J Rahme, Bradley E Bernstein, Ralph J DeBerardinis, Itay Tirosh, Mario L Suvà, Lin Xu, Kalil G Abdullah, Samuel K McBrayer.
      Isocitrate dehydrogenase ( IDH ) mutations arise early in gliomas and are associated with a defined neurodevelopmental cancer cell hierarchy. However, how mutant IDH contributes to this hierarchy and whether this interaction promotes gliomagenesis remain unclear. We captured the dynamics of IDH-mutant glioma initiation in genetically engineered mice through time-resolved, single-cell genomics. Mutant IDH activates and induces lineage switching of neural progenitor cells (NPCs). These actions expand oligodendrocyte precursor cells, the predominant cell-of-origin for these tumors, at the expense of interneurons. Lineage switching is mediated by promoter hypermethylation and silencing of Gsx2 , a homeobox gene required for neurogenesis. Critically, Gsx2 ablation recapitulates NPC fate reprogramming by mutant IDH. We provide a new model of neural cell fate control by IDH oncogenes and insights into the developmental origins of glioma.
    DOI:  https://doi.org/10.1101/2025.08.12.667486
  2. Oncogene. 2025 Aug 18.
    Membrane flexibility induced by BST2 contributes to radioresistance in glioblastoma.
    Haksoo Lee, Dahye Kim, Byeongsoo Kim, Eunguk Shin, Hyunkoo Kang, Jae-Myung Lee, HyeSook Youn, BuHyun Youn.
      Glioblastoma (GBM) is an aggressive brain tumor with a poor prognosis due to its resistance to radiotherapy. Epidermal growth factor receptor variant III (EGFRvIII), a common mutation in GBM, promotes radioresistance through ligand-independent activation. We hypothesized that membrane flexibility influences EGFRvIII activation and enhances resistance. Bone marrow stromal antigen 2 (BST2, CD317, or TETHERIN) was identified as a key mediator linking membrane dynamics to EGFRvIII-driven survival signaling. Radiation-induced changes in membrane flexibility amplified BST2 activity, stabilizing lipid rafts and promoting EGFRvIII clustering. Pharmacological inhibition of BST2 with arbutin, an FDA-approved compound, disrupted this mechanism, increasing GBM radiosensitivity by enhancing mitochondrial reactive oxygen species (ROS) production and apoptosis. Additionally, BST2 downregulation impaired de novo lipogenesis and reduced lipid droplet accumulation, highlighting its role in metabolic reprogramming. In orthotopic xenograft models, BST2 inhibition suppressed tumor growth and prolonged survival. These findings establish BST2 as a key regulator of membrane-driven radioresistance in GBM. Targeting BST2-mediated membrane remodeling may provide a novel therapeutic strategy to enhance radiotherapy efficacy.
    DOI:  https://doi.org/10.1038/s41388-025-03544-4
  3. Nat Commun. 2025 Aug 18. 16(1): 7672
    Bioengineered hybrid dual-targeting nanoparticles reprogram the tumour microenvironment for deep glioblastoma photodynamic therapy.
    Rongrong Zhao, Ying Hou, Boyan Li, Ziwen Pan, Jiawei Qiu, Qingtong Wang, Yanhua Qi, Zhe Han, Hongyu Zhao, Hong Liu, Weijia Zhou, Gang Li, Hao Xue.
      Glioblastoma (GBM) poses significant therapeutic challenges due to its hypoxic and immunosuppressive tumour microenvironment (TME), low immunogenicity and physical barriers. While combining photodynamic therapy (PDT) with immunotherapy holds promise, its efficacy is hampered by insufficient immune activation. In this study, we develop a multifunctional photodynamic-enhanced biomimetic intelligent nanoplatform (FBFO@HM@aOPN) responsive to the TME. The nanoplatform consists of a dual-enzyme nanozyme encapsulated in a prokaryotic-eukaryotic hybrid membrane, further modified with a pH-sensitive tumor-targeting antibody. After systemic administration, FBFO@HM@aOPN selectively accumulates in the GBM through vascular regulation and extracellular matrix (ECM) remodelling while generating oxygen to alleviate hypoxia. Crucially, the platform concurrently induces immunogenic death in tumour cells and reprograms protumoral macrophages to antitumor phenotypes. This dual action robustly activates both innate and adaptive immunity, significantly inhibiting GBM growth. Furthermore, when combined with anti-PD1 immunotherapy, the nanoplatform dramatically boosts the treatment effect and effectively prevents postsurgical tumour recurrence. Therefore, our work offers a multimodal platform for stimulating anti-tumour immunity, with potential applicability for GBM patients.
    DOI:  https://doi.org/10.1038/s41467-025-63081-2
  4. Nat Cell Biol. 2025 Aug 19.
    Systematic decoding of functional enhancer connectomes and risk variants in human glioma.
    Jinfang Bi, Weipeng Mo, Man Liu, Yingjie Song, Qian Xiao, Sibo Fan, Wenbin Wang, Tengfei Shi, Yaoqiang Zheng, Jie Lian, Rong Liu, Bohan Chen, Xiaofeng Huang, Peng Li, Zhongfang Zhao, Jiandang Shi, Lei Zhang, Guangsong Su, Nu Zhang, Wange Lu.
      Genetic and epigenetic variations contribute to the progression of glioma, but the mechanisms underlying these effects, particularly for enhancer-associated genetic variations in non-coding regions, still remain unclear. Here we performed high-throughput CRISPR interference screening to identify pro-tumour enhancers in glioma cells. By integrating genome-wide H3K27ac HiChIP data, we identified the target genes of these pro-tumour enhancers and revealed the essential role of enhancer connectomes in promoting glioma progression. Through systematic analysis of enhancers carrying glioma risk-associated single-nucleotide polymorphisms (SNPs), we found that these SNPs can promote glioma progression through the enhancer connectome. Using CRISPR-Cas9-mediated enhancer interference and SNP editing, we demonstrated that glioma-specific enhancer carrying the risk SNP rs2297440 regulates SOX18 expression by specifically recruiting transcription factor MEIS1 binding, thereby contributing to glioma progression. Our study sheds light on the molecular mechanisms underlying glioma susceptibility and provides potential therapeutic targets to treat glioma.
    DOI:  https://doi.org/10.1038/s41556-025-01737-3
  5. Neuro Oncol. 2025 Aug 13. pii: noaf192. [Epub ahead of print]
    Revisiting an old therapy for new, promising combinations: biology and perspectives of lomustine in glioma treatment.
    Charlotte Bellamy, Cynthia Hajal, Keith L Ligon, Mehdi Touat.
      The alkylating agents temozolomide (TMZ) and lomustine (CCNU) are the most effective systemic agents for malignant gliomas. However, resistance - whether intrinsic or acquired - inevitably develops in all patients, and these tumors remain incurable. Although CCNU has demonstrated clinical benefit, its clinical use has been relatively limited due to a less favorable safety profile compared to TMZ. Recently, interest in CCNU and other nitrosoureas has been renewed in light of positive clinical trials in both adult and pediatric gliomas. Despite this renewed attention, critical questions remain unaddressed regarding the use of nitrosoureas. While resistance and response to temozolomide have been associated with the status of both MGMT and the mismatch repair DNA repair pathway, our understanding of the unique mechanisms of resistance to nitrosoureas beyond MGMT remains limited. Recent advances in molecular biology, preclinical models and the use of longitudinal analyses of treated samples offer new insights, offering opportunities to refine the clinical and develop novel strategies. In this review, we explore the current role of nitrosoureas in glioma treatment, examine known and emerging mechanisms of sensitivity and resistance to these agents, and explore potential for combination approaches to enhance their efficacy.
    Keywords:  Chemotherapy; DNA damage; biomarkers; glioma; precision medicine; resistance
    DOI:  https://doi.org/10.1093/neuonc/noaf192
  6. Cancer Cell. 2025 Aug 12. pii: S1535-6108(25)00330-7. [Epub ahead of print]
    Long-range cholinergic input promotes glioblastoma progression.
    Yang Yang, Chuanyan Yang, Xuezhu Chen, Yibin Jiang, Xuejiao Lei, Kang Ma, Yulian Quan, Tianran Li, Chenfu Guo, Yijing Meng, Lin Kang, Xinyu Zhang, Long Jin, Jiafeng Huang, Ning Mu, Zexuan Yan, Qinghua Ma, Shuai Wang, Yanxia Wang, Yong-Ning Shang, Cong Chen, Yu Shi, Shukun Hu, Likun Yang, Chuan Lan, Rong Hu, Ying Zhang, Xia Li, Yunqing Li, Chong Liu, Yu-Hai Wang, Fei Li, Hua Feng, Xiu-Wu Bian, Tunan Chen.
      Glioblastoma (GBM), the most aggressive primary brain tumor, is shaped by its integration into neural networks. While glutamatergic input is linked to tumor progression, the broader architecture and function of neuron-glioma connectomes remain unclear. Using monosynaptic rabies tracing, we map brain-wide neural input to patient-derived xenografts and reveal a consistent organizational logic: local inputs are primarily glutamatergic, while long-range connections exhibit diverse neurotransmitter profiles, with basal forebrain cholinergic projections emerging as a conserved input across sites. Functionally, presynaptic acetylcholine release promotes GBM progression through muscarinic receptor CHRM3 in a circuit-specific manner. Mechanistically, glutamatergic and cholinergic signals converge to enhance glioma calcium transients but diverge in temporal transcriptional control, with their dual blockade producing additive anti-tumor effects. Therapeutically, the anticholinergic drug scopolamine attenuates glioma growth, whereas the acetylcholinesterase inhibitor donepezil exacerbates disease. These findings reveal the complexity of neuron-glioma connectivity, highlighting long-range neuromodulatory pathways as promising therapeutic targets in GBM.
    Keywords:  CHRM3; cholinergic input; diagonal band of Broca; donepezil; glioblastoma; glutamatergic input; neural circuit manipulation; neuro-glioma interaction; rabies virus; scopolamine
    DOI:  https://doi.org/10.1016/j.ccell.2025.07.024
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