bims-malgli Biomed News
on Biology of malignant gliomas
Issue of 2025–02–09
eleven papers selected by
Oltea Sampetrean, Keio University
  1. Cuproplasia-related gene signature: Prognostic insights for glioma therapy.
  2. Cellular senescence-associated gene IFI16 promotes HMOX1-dependent evasion of ferroptosis and radioresistance in glioblastoma.
  3. Immunocompetent murine glioblastoma stem-like cell models exhibiting distinct phenotypes.
  4. GBMPurity: A Machine Learning Tool for Estimating Glioblastoma Tumour Purity from Bulk RNA-seq Data.
  5. Druggable genome CRISPRi screen in 3D hydrogels reveals regulators of cortactin-driven actin remodeling in invading glioblastoma cells.
  6. Overcoming immune evasion with innovative multi-target approaches for glioblastoma.
  7. Vaccine-induced T cell receptor T cell therapy targeting a glioblastoma stemness antigen.
  8. A Material Transfer Agreement between Glioblastoma and Normal Brain Cells.
  9. Exploiting metabolic vulnerability in glioblastoma using a brain-penetrant drug with a safe profile.
  10. Circadian rhythm related genes signature in glioma for drug resistance prediction: a comprehensive analysis integrating transcriptomics and machine learning.
  11. D-2-hydroxyglutarate impairs DNA repair through epigenetic reprogramming.
  1. Neurooncol Adv. 2025 Jan-Dec;7(1):7(1): vdae233
    Cuproplasia-related gene signature: Prognostic insights for glioma therapy.
    Toni Rose Jue, Joseph Descallar, Vu Viet Hoang Pham, Jessica Lilian Bell, Tyler Shai-Hee, Riccardo Cazzolli, Sumanth Nagabushan, Eng-Siew Koh, Orazio Vittorio.
       Background: Adult-type diffuse gliomas encompass nearly a quarter of all primary tumors found in the CNS, including astrocytoma, oligodendroglioma, and glioblastoma. Histopathological tumor grade and molecular profile distinctly impact patient survival. Despite treatment advancements, patients with recurrent glioma have a very poor clinical outcome, warranting improved risk stratification to determine therapeutic interventions. Various studies have shown that copper is a notable trace element that is crucial for biological processes and has been shown to display pro-tumorigenic functions in cancer, particularly gliomas.
    Methods: Differential gene expression, Cox regression, and least absolute shrinkage and selection operator regression were used to identify 19 copper-homeostasis-related gene signatures using TCGA lower-grade glioma and glioblastoma (GBM) cohorts. The GLASS Consortium dataset was used as an independent validation cohort. Enrichment analysis revealed the involvement of the signature in various cancer-related pathways and biological processes. Using this CHRG signature, a risk score model and a nomogram were developed to predict survival in glioma patients.
    Results: Our prognostic CHRG signature stratified patients into high- and low-risk groups, demonstrating robust predictive performance. High-risk groups showed poorer survival outcomes. The nomogram model integrating CHRG signature and clinical features accurately predicted 1-, 3-, and 5-year survival rates in both training and test sets.
    Conclusions: The identified 19-gene CHRG signature holds promise as a prognostic tool, enabling accurate risk stratification and survival prediction in glioma patients. Integrating this signature with clinical characteristics enhances prognostic accuracy, underscoring its potential clinical utility in optimizing therapeutic strategies and patient care in glioma management.
    Keywords:  copper; cuproplasia; glioma; immunotherapy; personalized medicine
    DOI:  https://doi.org/10.1093/noajnl/vdae233
  2. Nat Commun. 2025 Jan 31. 16(1): 1212
    Cellular senescence-associated gene IFI16 promotes HMOX1-dependent evasion of ferroptosis and radioresistance in glioblastoma.
    Yuchuan Zhou, Liang Zeng, Linbo Cai, Wang Zheng, Xinglong Liu, Yuqi Xiao, Xiaoya Jin, Yang Bai, Mingyao Lai, Hainan Li, Hua Jiang, Songling Hu, Yan Pan, Jianghong Zhang, Chunlin Shao.
      Glioblastoma multiforme (GBM) remains a therapeutic challenge due to its aggressive nature and recurrence. This study establishes a radioresistant GBM cell model through repeated irradiation and observes a cellular senescence-like phenotype in these cells. Comprehensive genomic and transcriptomic analyses identify IFI16 as a central regulator of this phenotype and contributes to radioresistance. IFI16 activates HMOX1 transcription thereby attenuating ferroptosis by reducing lipid peroxidation, ROS production, and intracellular Fe2+ content following irradiation. Furthermore, IFI16 interacts with the transcription factors JUND and SP1 through its pyrin domain, robustly facilitating HMOX1 expression, further inhibiting ferroptosis and enhancing radioresistance in GBM. Notably, glyburide, a sulfonylurea compound, effectively disrupts IFI16 function and enhances ferroptosis and radiosensitivity. By targeting the pyrin domain of IFI16, glyburide emerges as a potential therapeutic agent against GBM radioresistance. These findings underscore the central role of IFI16 in GBM radioresistance and offer promising avenues to improve GBM treatment.
    DOI:  https://doi.org/10.1038/s41467-025-56456-y
  3. Neurooncol Adv. 2025 Jan-Dec;7(1):7(1): vdae215
    Immunocompetent murine glioblastoma stem-like cell models exhibiting distinct phenotypes.
    Kimia Kardani, Shanawaz M Ghouse, Muzammil Arif Din Abdul Jabbar, Namita Rajasubramanian, Judit Sanchez Gil, Anat Stemmer-Rachamimov, Yasushi Soda, Robert L Martuza, Toshiro Hara, Hiroaki Wakimoto, Samuel D Rabkin.
       Background: Glioblastoma (GBM) treatment is hindered by a dearth of representative mouse GBM preclinical models in immunocompetent mice. Here, we characterized 5 murine GBM stem-like cell (mGSC) models derived from lentivirus-induced tumors in transgenic mice that are driven by the activation of the Nf1-Ras signaling pathway and inactivation of Tp53.
    Methods: MGSC lines (005, RIG, NF53, C1, and C3) were cultured as spheres in serum-free stem cell media. Whole exome sequencing (WES) was employed to quantify single nucleotide polymorphisms (SNPs). Stem cell properties were characterized by stemness in vitro and tumorigenicity after intracerebral implantation in C57BL/6 mice. Tumor phenotypes and the immune microenvironment were characterized by immunohistochemistry, flow cytometry, and RNA sequencing.
    Results: WES revealed a large variation in coding sequence SNPs across mGSC lines (~20-fold), likely influenced by the mixed backgrounds of the parental mice. MGSCs exhibited variable clonogenic sphere formation and CD133 expression levels. In vivo, they consistently initiated lethal malignant gliomas, with median survival ranging from 29 to 82 days, and showed strong CD44 expression and variable invasiveness. The tumor microenvironment featured an abundance of CD68+ macrophages and uniform high PD-L1+ myeloid cells, while T-cell infiltration varied among the models, with low mutation burden C1 and C3 exhibiting fewer tumor-infiltrating T cells.
    Conclusions: Upon orthotopic implantation in immunocompetent mice, mGSCs generate tumors characteristic of human GBM. Despite similar strategies to generate these mGSCs, they exhibited a range of phenotypes and immune profiles in mGSC-derived orthotopic tumors. These mGSCs provide new preclinical GBM models for developing GBM immunotherapies.
    Keywords:  GBM; GSC; glioblastoma stem-like cells; immunocompetent GBM model; tumor microenvironment
    DOI:  https://doi.org/10.1093/noajnl/vdae215
  4. Neuro Oncol. 2025 Feb 01. pii: noaf026. [Epub ahead of print]
    GBMPurity: A Machine Learning Tool for Estimating Glioblastoma Tumour Purity from Bulk RNA-seq Data.
    Morgan P H Thomas, Shoaib Ajaib, Georgette Tanner, Andrew J Bulpitt, Lucy F Stead.
       BACKGROUND: Glioblastoma (GBM) presents a significant clinical challenge due to its aggressive nature and extensive heterogeneity. Tumour purity, the proportion of malignant cells within a tumour, is an important covariate for understanding the disease, having direct clinical relevance or obscuring signal of the malignant portion in molecular analyses of bulk samples. However, current methods for estimating tumour purity are non-specific and technically demanding. Therefore, we aimed to build a reliable and accessible purity estimator for GBM.
    METHODS: We developed GBMPurity, a deep-learning model specifically designed to estimate the purity of IDH-wildtype primary GBM from bulk RNA-seq data. The model was trained using simulated pseudobulk tumours of known purity from labelled single-cell data acquired from the GBmap resource. The performance of GBMPurity was evaluated and compared to several existing tools using independent datasets.
    RESULTS: GBMPurity outperformed existing tools, achieving a mean absolute error of 0.15 and a concordance correlation coefficient of 0.88 on validation datasets. We demonstrate the utility of GBMPurity through inference on bulk RNA-seq samples and observe reduced purity of the Proneural molecular subtype relative to the Classical, attributed to the increased presence of healthy brain cells.
    CONCLUSIONS: GBMPurity provides a reliable and accessible tool for estimating tumour purity from bulk RNA-seq data, enhancing the interpretation of bulk RNA-seq data and offering valuable insights into GBM biology. To facilitate the use of this model by the wider research community, GBMPurity is available as a web-based tool at: https://gbmdeconvoluter.leeds.ac.uk/.
    Keywords:  Glioblastoma; deconvolution; transcriptomics; tumour microenvironment; tumour purity
    DOI:  https://doi.org/10.1093/neuonc/noaf026
  5. bioRxiv. 2025 Jan 24. pii: 2025.01.20.633978. [Epub ahead of print]
    Druggable genome CRISPRi screen in 3D hydrogels reveals regulators of cortactin-driven actin remodeling in invading glioblastoma cells.
    Mufeng Hu, Anna Weldy, Isabella Lovalvo, Erin Akins, Saket Jain, Alexander Chang, Ankita Sati, Meeki Lad, Austin Lui, Akhil Rajidi, Ameya Kothekar, Erika Ding, Sanjay Kumar, Manish K Aghi.
      To identify new therapeutic targets that limit glioblastoma (GBM) invasion, we applied druggable-genome CRISPR screens to patient-derived GBM cells in micro-dissectible biomimetic 3D hydrogel platforms that permit separation and independent analysis of core vs. invasive fractions. We identified 12 targets whose suppression limited invasion, of which ACP1 (LMW-PTP) and Aurora Kinase B (AURKB) were validated in neurosphere assays. Proximity labeling analysis identified cortactin as an ACP1- AURKB link, as cortactin undergoes serine phosphorylation by AURKB and tyrosine dephosphorylation by ACP1. Suppression of ACP1 or AURKB in culture and in vivo shifted the balance of cortactin phosphorylation in GBM and reduced actin polymerization and actin-cortactin co-localization. Additional biophysical analysis implicated AURKB in GBM cell adhesion and cortical stiffness, and ACP1 in resistance to mechanical stress and shape plasticity needed for 3D migration. These findings reveal a novel targetable axis that balances kinase and phosphatase activities to regulate actin polymerization during GBM invasion.
    DOI:  https://doi.org/10.1101/2025.01.20.633978
  6. Front Immunol. 2025 ;16 1541467
    Overcoming immune evasion with innovative multi-target approaches for glioblastoma.
    Hai Su, Yin Peng, Yilong Wu, Xiaoli Zeng.
      Glioblastoma (GBM) cells leverage complex endogenous and environmental regulatory mechanisms to drive proliferation, invasion, and metastasis. Tumor immune evasion, facilitated by a multifactorial network, poses a significant challenge to effective therapy, as evidenced by the limited clinical benefits of monotherapies, highlighting the adaptive nature of immune evasion. This review explores glioblastoma's immune evasion mechanisms, the role of ICIs in the tumor microenvironment, and recent clinical advancements, offering theoretical insights and directions for monotherapy and combination therapy in glioblastoma management.
    Keywords:  PD-1; glioblastoma; immune checkpoint; immune evasion; immunotherapy
    DOI:  https://doi.org/10.3389/fimmu.2025.1541467
  7. Nat Commun. 2025 Feb 01. 16(1): 1262
    Vaccine-induced T cell receptor T cell therapy targeting a glioblastoma stemness antigen.
    Yu-Chan Chih, Amelie C Dietsch, Philipp Koopmann, Xiujian Ma, Dennis A Agardy, Binghao Zhao, Alice De Roia, Alexandros Kourtesakis, Michael Kilian, Christopher Krämer, Abigail K Suwala, Miriam Stenzinger, Halvard Boenig, Agnieszka Blum, Victor Murcia Pienkowski, Kuralay Aman, Jonas P Becker, Henrike Feldmann, Theresa Bunse, Richard Harbottle, Angelika B Riemer, Hai-Kun Liu, Nima Etminan, Felix Sahm, Miriam Ratliff, Wolfgang Wick, Michael Platten, Edward W Green, Lukas Bunse.
      T cell receptor-engineered T cells (TCR-T) could be advantageous in glioblastoma by allowing safe and ubiquitous targeting of the glioblastoma-derived peptidome. Protein tyrosine phosphatase receptor type Z1 (PTPRZ1), is a clinically targetable glioblastoma antigen associated with glioblastoma cell stemness. Here, we identify a therapeutic HLA-A*02-restricted PTPRZ1-reactive TCR retrieved from a vaccinated glioblastoma patient. Single-cell sequencing of primary brain tumors shows PTPRZ1 overexpression in malignant cells, especially in glioblastoma stem cells (GSCs) and astrocyte-like cells. The validated vaccine-induced TCR recognizes the endogenously processed antigen without off-target cross-reactivity. PTPRZ1-specific TCR-T (PTPRZ1-TCR-T) kill target cells antigen-specifically, and in murine experimental brain tumors, their combined intravenous and intracerebroventricular administration is efficacious. PTPRZ1-TCR-T maintain stem cell memory phenotype in vitro and in vivo and lyse all examined HLA-A*02+ primary glioblastoma cell lines with a preference for GSCs and astrocyte-like cells. In summary, we demonstrate the proof of principle to employ TCR-T to treat glioblastoma.
    DOI:  https://doi.org/10.1038/s41467-025-56547-w
  8. Cancer Discov. 2025 Feb 07. 15(2): 261-263
    A Material Transfer Agreement between Glioblastoma and Normal Brain Cells.
    Sajina Shakya, Christopher G Hubert, Justin D Lathia.
      Tumor cells communicate with normal cells in various ways, typically leading to the exploitation of resources of the normal cells by tumor cells for their benefit. In this issue, Mangena and colleagues use three-dimensional organoid models to show the transfer of GFP and mRNA from malignant glioblastoma to nonmalignant cells in cerebral organoid models; this transfer is facilitated by extracellular vesicles and possibly tunneling nanotubes, demonstrating how nonmalignant cells in the tumor microenvironment can be exploited by neighboring malignant cells. See related article by Mangena et al., p. 299.
    DOI:  https://doi.org/10.1158/2159-8290.CD-24-1661
  9. EMBO Mol Med. 2025 Feb 03.
    Exploiting metabolic vulnerability in glioblastoma using a brain-penetrant drug with a safe profile.
    Audrey Burban, Cloe Tessier, Mathieu Larroquette, Joris Guyon, Cloe Lubiato, Mathis Pinglaut, Maxime Toujas, Johanna Galvis, Benjamin Dartigues, Emmanuelle Georget, H Artee Luchman, Samuel Weiss, David Cappellen, Nathalie Nicot, Barbara Klink, Macha Nikolski, Lucie Brisson, Thomas Mathivet, Andreas Bikfalvi, Thomas Daubon, Ahmad Sharanek.
      Glioblastoma is one of the most treatment-resistant and lethal cancers, with a subset of self-renewing brain tumour stem cells (BTSCs), driving therapy resistance and relapse. Here, we report that mubritinib effectively impairs BTSC stemness and growth. Mechanistically, bioenergetic assays and rescue experiments showed that mubritinib targets complex I of the electron transport chain, thereby impairing BTSC self-renewal and proliferation. Gene expression profiling and Western blot analysis revealed that mubritinib disrupts the AMPK/p27Kip1 pathway, leading to cell-cycle impairment. By employing in vivo pharmacokinetic assays, we established that mubritinib crosses the blood-brain barrier. Using preclinical patient-derived and syngeneic models, we demonstrated that mubritinib delays glioblastoma progression and extends animal survival. Moreover, combining mubritinib with radiotherapy or chemotherapy offers survival advantage to animals. Notably, we showed that mubritinib alleviates hypoxia, thereby enhancing ROS generation, DNA damage, and apoptosis in tumours when combined with radiotherapy. Encouragingly, toxicological and behavioural studies revealed that mubritinib is well tolerated and spares normal cells. Our findings underscore the promising therapeutic potential of mubritinib, warranting its further exploration in clinic for glioblastoma therapy.
    Keywords:  Hypoxia; Metabolic Reliance; Oxidative Phosphorylation; Radiotherapy; Reactive Oxygen Species
    DOI:  https://doi.org/10.1038/s44321-025-00195-6
  10. Discov Oncol. 2025 Feb 05. 16(1): 119
    Circadian rhythm related genes signature in glioma for drug resistance prediction: a comprehensive analysis integrating transcriptomics and machine learning.
    Junbo Liao, Yingxing Duan, Xiangwang Xu, Yaxue Liu, Chaohong Zhan, Gelei Xiao.
       BACKGROUND: Gliomas, 24% of all primary brain tumors, have diverse histology and poor survival rates, with about 70% recurring due to acquired or de novo resistance. Insomnia in patients is correlated strongly with circadian rhythm disruptions. The correlation between circadian rhythm disorders and drug resistance of some tumors has been proved. However, the precise mechanism underlying the relationship between glioma and circadian rhythm disorders has not been elucidated.
    METHODS: Circadian rhythm-related genes (CRRGs) were identified using the least absolute shrinkage and selection operator (LASSO) regression, and stochastic gradient descent (SGD) was performed to form a circadian rhythm-related score (CRRS) model. The studies of immune cell infiltration, genetic variations, differential gene expression pattern, and single cell analysis were performed for exploring the mechanisms of chemotherapy resistance in glioma. The relationship between CRRGs and chemosensitivity was also confirmed by IC 50 (half maximal inhibitory concentration) analysis.
    RESULT: Signatures of 16 CRRGs were screened out and identified. Based on the CRRS model, an optimal comprehensive nomogram was created, exhibiting a favorable potential for predicting drug resistance in samples. Immune infiltration, cell-cell communication, and single cell analysis all indicated that high CRRS group was closely related to innate immune cells. IC50 analysis showed that CRRG knockdown enhanced the chemosensitivity of glioma.
    CONCLUSION: A significant correlation between CRRGs, drug resistance of glioma, and innate immune cells was found, which might hold a significant role in the drug resistance of glioma.
    Keywords:  Chemotherapy; Circadian rhythm; Drug resistance; Glioma; Innate immune
    DOI:  https://doi.org/10.1007/s12672-025-01863-2
  11. Nat Commun. 2025 Feb 07. 16(1): 1431
    D-2-hydroxyglutarate impairs DNA repair through epigenetic reprogramming.
    Fengchao Lang, Karambir Kaur, Haiqing Fu, Javeria Zaheer, Diego Luis Ribeiro, Mirit I Aladjem, Chunzhang Yang.
      Cancer-associated mutations in IDH are associated with multiple types of human malignancies, which exhibit distinctive metabolic reprogramming, production of oncometabolite D-2-HG, and shifted epigenetic landscape. IDH mutated malignancies are signatured with "BRCAness", highlighted with the sensitivity to DNA repair inhibitors and genotoxic agents, although the underlying molecular mechanism remains elusive. In the present study, we demonstrate that D-2-HG impacts the chromatin conformation adjustments, which are associated with DNA repair process. Mechanistically, D-2-HG diminishes the chromatin interactions in the DNA damage regions via revoking CTCF binding. The hypermethylation of cytosine, resulting from the suppression of TET1 and TET2 activities by D-2-HG, contributes to the dissociation of CTCF from DNA damage regions. CTCF depletion leads to the disruption of chromatin organization around the DNA damage sites, which abolishes the recruitment of essential DNA damage repair proteins BRCA2 and RAD51, as well as impairs homologous repair in the IDH mutant cancer cells. These findings provide evidence that CTCF-mediated chromatin interactions play a key role in DNA damage repair proceedings. Oncometabolites jeopardize genome stability and DNA repair by affecting high-order chromatin structure.
    DOI:  https://doi.org/10.1038/s41467-025-56781-2
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