bims-malgli Biomed News
on Biology of malignant gliomas
Issue of 2025–05–04
nine papers selected by
Oltea Sampetrean, Keio University
  1. A zinc transporter drives glioblastoma progression via extracellular vesicles-reprogrammed microglial plasticity.
  2. Improved overall survival in an anti-PD-L1 treated cohort of newly diagnosed glioblastoma patients is associated with distinct immune, mutation, and gut microbiome features: a single arm prospective phase I/II trial.
  3. Investigative needle core biopsies support multimodal deep-data generation in glioblastoma.
  4. Single-nucleus RNA sequencing reveals a preclinical model for the most common subtype of glioblastoma.
  5. Charting the Single-Cell and Spatial Landscape of IDH-Wildtype Glioblastoma with GBmap.
  6. Mind Over Microbes: Targeting the Gut-Brain Axis to Improve Treatment of Pediatric Low-Grade Glioma.
  7. Combination of Sodium Butyrate and Immunotherapy in Glioma: regulation of immunologically hot and cold tumors via gut microbiota and metabolites.
  8. Gut microbiota and their influence in brain cancer milieu.
  9. The TCR Repertoire: A Window Into Pediatric Brain Tumor Immunity.
  1. Proc Natl Acad Sci U S A. 2025 May 06. 122(18): e2427073122
    A zinc transporter drives glioblastoma progression via extracellular vesicles-reprogrammed microglial plasticity.
    Liyang Zhang, Jingxuan Yang, Zhijun Zhou, Yu Ren, Bo Chen, Anliu Tang, Kailiang Zhang, Chuntao Li, Hongshu Zhou, Kar-Ming Fung, Chao Xu, Chunsheng Kang, James D Battiste, Michael S Bronze, Courtney W Houchen, Zhixiong Liu, Ian F Dunn, Webster K Cavenee, Min Li.
      Glioblastoma (GBM) is the most aggressive form of brain cancer, with limited therapeutic options. While microglia contribute to GBM progression, the mechanisms by which they foster a protumorigenic immune environment remain poorly understood. We identify the zinc transporter Zrt- And Irt-Like Protein 4 (ZIP4) as a pivotal regulator of the GBM immune landscape. In orthotopic mouse models, ZIP4 drives tumor growth and behavioral changes. Mechanistically, ZIP4 modulates microglial plasticity through tumor-derived extracellular vesicles carrying triggering receptor expressed on myeloid cells-1 (TREM1), a process regulated by the zinc-dependent transcription factor Zinc Finger E-box Binding Homeobox 1 in GBM cells. TREM1 enhances microglial plasticity through the spleen associated tyrosine kinase-Pyruvate dehydrogenase kinase-signal transducer and activator of transcription 3 (SYK-PDK-STAT3) signaling axis, ultimately promoting an immune environment favorable to tumor progression. ZIP4 depletion or TREM1 inhibition attenuates tumor growth and behavioral effects in vivo by disrupting the tumor-microglia interaction. These findings establish ZIP4 as a key modulator of the GBM immune landscape and suggest a promising therapeutic target to counteract microglia-mediated tumor progression.
    Keywords:  TREM1; exosome; glioblastoma; microglia
    DOI:  https://doi.org/10.1073/pnas.2427073122
  2. Nat Commun. 2025 Apr 27. 16(1): 3950
    Improved overall survival in an anti-PD-L1 treated cohort of newly diagnosed glioblastoma patients is associated with distinct immune, mutation, and gut microbiome features: a single arm prospective phase I/II trial.
    Shiao-Pei Weathers, Xiqi Li, Haifeng Zhu, Ashish V Damania, Mark Knafl, Brian McKinley, Heather Lin, Rebecca A Harrison, Nazanin K Majd, Barbara J O'Brien, Marta Penas-Prado, Monica Loghin, Carlos Kamiya-Matsuoka, W K Alfred Yung, Luisa M Solis Soto, Dipen M Maru, Ignacio Wistuba, Edwin R Parra Cuentas, Sharia Hernandez, Andrew Futreal, Jennifer A Wargo, Katja Schulze, Walter C Darbonne, Nadim J Ajami, Scott E Woodman, John F de Groot.
      This phase I/II trial aims to evaluate the efficacy of concurrent atezolizumab with radiation therapy and temozolomide (TMZ) followed by adjuvant atezolizumab and TMZ in newly diagnosed glioblastoma (GBM) patients and to identify pre-treatment correlates with outcome (N = 60). Trial number: NCT03174197. The primary outcome was overall survival (OS) whereas secondary outcomes were retrospective global-omics analyses to identify pre-treatment immune and genetic tumor features that correlated with survival. Concurrent use of atezolizumab with radiation and TMZ demonstrated OS in line with published trials for newly diagnosed GBM. Tumor genomic (WES and/or targeted NGS panel), transcriptomic (RNAseq) and tissue microenvironment imaging, as well as fecal metagenomic sequencing were conducted. Gene set enrichment analysis of tumors identified multiple immune-based transcriptomic programs to distinguish patients with longer versus shorter survival (p ≤ 0.01). GBM immune enrichment was highly associated with the pre-treatment tumor mesenchymal subtype and patient gastrointestinal bacterial taxa profile.
    DOI:  https://doi.org/10.1038/s41467-025-56930-7
  3. Nat Commun. 2025 Apr 28. 16(1): 3957
    Investigative needle core biopsies support multimodal deep-data generation in glioblastoma.
    GBM TeamLab
      Glioblastoma (GBM) is an aggressive primary brain cancer with few effective therapies. Stereotactic needle biopsies are routinely used for diagnosis; however, the feasibility and utility of investigative biopsies to monitor treatment response remains ill-defined. Here, we demonstrate the depth of data generation possible from routine stereotactic needle core biopsies and perform highly resolved multi-omics analyses, including single-cell RNA sequencing, spatial transcriptomics, metabolomics, proteomics, phosphoproteomics, T-cell clonotype analysis, and MHC Class I immunopeptidomics on standard biopsy tissue obtained intra-operatively. We also examine biopsies taken from different locations and provide a framework for measuring spatial and genomic heterogeneity. Finally, we investigate the utility of stereotactic biopsies as a method for generating patient-derived xenograft (PDX) models. Multimodal dataset integration highlights spatially mapped immune cell-associated metabolic pathways and validates inferred cell-cell ligand-receptor interactions. In conclusion, investigative biopsies provide data-rich insight into disease processes and may be useful in evaluating treatment responses.
    DOI:  https://doi.org/10.1038/s41467-025-58452-8
  4. Commun Biol. 2025 Apr 28. 8(1): 671
    Single-nucleus RNA sequencing reveals a preclinical model for the most common subtype of glioblastoma.
    Laura García-Vicente, María Martínez-Fernández, Michael Borja, Vanessa Tran, Andrea Álvarez-Vázquez, Raquel Flores-Hernández, Yuxin Ding, Raúl González-Sánchez, Alejandro Granados, Erin McGeever, Yang-Joon Kim, Angela Detweiler, Honey Mekonen, Sheryl Paul, Angela O Pisco, Norma F Neff, Arantxa Tabernero.
      Different glioblastoma (GBM) subtypes have been identified based on the tumor microenvironment (TME). The discovery of new therapies for these hard-to-treat tumors requires a thorough characterization of preclinical models, including their TME, to apply preclinical results to the most similar GBM subtype. Using single-nucleus RNA sequencing (snRNA-seq), we characterized the tumor and TME in an immunocompetent mouse model with intracranially implanted GBM stem cells at different stages and treatments. Visium spatial transcriptomics confirmed the location of annotated cells. This model exhibits GBM targets related to integration into neural circuits - Grik2, Nlgn3, Gap43 or Kcnn4-, immunoevasion - Nt5e, Cd274 or Irf8- and immunosuppression - Csf1r, Arg1, Mrc1 and Tgfb1. The landscape of cytokines, checkpoint ligands and receptors uncovered Mrc1, PD-L1, TIM-3 or B7-H3, among the immunotherapy targets that can be addressed in this model. The comparison with human GBMs unveiled crucial similarities with TMEMed GBM, the most frequent subtype.
    DOI:  https://doi.org/10.1038/s42003-025-08092-x
  5. Neuro Oncol. 2025 May 02. pii: noaf113. [Epub ahead of print]
    Charting the Single-Cell and Spatial Landscape of IDH-Wildtype Glioblastoma with GBmap.
    Cristian Ruiz-Moreno, Sergio Marco Salas, Erik Samuelsson, Mariia Minaeva, Ignacio Ibarra, Marco Grillo, Sebastian Brandner, Ananya Roy, Karin Forsberg-Nilsson, Mariette E G Kranendonk, Fabian J Theis, Mats Nilsson, Hendrik G Stunnenberg.
       BACKGROUND: Glioblastoma (GB), particularly IDH-wildtype, is the most aggressive brain malignancy with a dismal prognosis. Despite advances in molecular profiling, the complexity of its tumor microenvironment and spatial organization remains poorly understood. This study aimed to create a comprehensive single-cell and spatial atlas of GB to unravel its cellular heterogeneity, spatial architecture, and clinical relevance.
    METHODS: We integrated single-cell RNA sequencing data from 26 datasets, encompassing over 1.1 million cells from 240 patients, to construct GBmap, a harmonized single-cell atlas. High-resolution spatial transcriptomics was employed to map the spatial organization of GB tissues. We developed the Tumor Structure Score (TSS) to quantify tumor organization and correlated it with patient outcomes.
    RESULTS: We showcase the applications of GBmap for reference mapping, transfer learning, and biological discoveries. GBmap revealed extensive cellular heterogeneity, identifying rare populations such as tumor-associated neutrophils and homeostatic microglia. Spatial analysis uncovered seven distinct tumor niches, with hypoxia-dependent niches strongly associated with poor prognosis. The TSS demonstrated that highly organized tumors, characterized by well-defined vasculature and hypoxic niches, correlated with worse survival outcomes.
    CONCLUSIONS: This study provides a comprehensive resource for understanding glioblastoma heterogeneity and spatial organization. GBmap and the TSS provide an integrative view of tumor architecture in GB, highlighting hypoxia-driven niches that may represent avenues for further investigation. Our resource can facilitate exploratory analyses and hypothesis generation to better understand disease progression.
    Keywords:  Glioblastoma; Hypoxia; Single-cell atlas; Spatial transcriptomics; Tumor organization
    DOI:  https://doi.org/10.1093/neuonc/noaf113
  6. Neuro Oncol. 2025 May 02. pii: noaf094. [Epub ahead of print]
    Mind Over Microbes: Targeting the Gut-Brain Axis to Improve Treatment of Pediatric Low-Grade Glioma.
    Vijay Ramaswamy, Uri Tabori.
      
    DOI:  https://doi.org/10.1093/neuonc/noaf094
  7. Front Immunol. 2025 ;16 1532528
    Combination of Sodium Butyrate and Immunotherapy in Glioma: regulation of immunologically hot and cold tumors via gut microbiota and metabolites.
    Sui Li, Li Wang, MingYu Han, Huali Fan, Hailin Tang, Huile Gao, Guobo Li, Zheng Xu, Zhaokai Zhou, JunRong Du, Cheng Peng, Fu Peng.
       Background: Recent studies have highlighted the importance of cross-talk along the gut-brain axis in regulating inflammatory nociception, inflammatory responses, and immune homeostasis. The gut microbiota, particularly its bacterial composition, plays a crucial role in the development and function of the immune system. Moreover, metabolites produced by the gut microbiota can significantly impact both systemic immune responses and central nervous system (CNS) immunity. Sodium butyrate is a key metabolite produced by the gut microbiota and, as a histone deacetylase inhibitor, can enhance the anti-tumor immunity of cytotoxic CD8+ T cells. However, it remains unclear whether sodium butyrate treatment can enhance the efficacy of PD-1 blockade in glioma therapy. In this research, the effect and underlying mechanism of combination of gut microbiota metabolites and anti-mouse PD-1 mAb on glioma has been investigated.
    Methods: RNA-seq assay in glioma cell and biomedical databases, including ONCOMINE, GEPIA and TCGA were incorporated. Subsequently, the inhibitory effect of sodium butyrate on glioma cells and its related mechanisms were assessed through Counting Kit-8 (CCK-8), Flow Cytometry, Western blot (WB), reverse transcription-quantitative polymerase chain reaction (RT-qPCR), and other in vitro experiments. In vitro, an orthotopic mouse glioma model was established. MRI imaging, Immunohistochemistry, and Immune cell flow cytometry were used to investigate the therapeutic effects of combined sodium butyrate and PD-1 inhibitor treatment on glioma-bearing mice.
    Results: We discovered that deacetylation-associated gene expression is significantly increased in glioma patients and affects patient survival time. Moreover, we found sodium butyrate promoted glioma cell apoptosis, disrupted the cell cycle, and inhibited tumor growth. Additionally, sodium butyrate may upregulate PD-L1 expression in glioma cells by modulating the PI3K/AKT pathway. The experimental results demonstrated that this combination therapy significantly reduced tumor volume and prolonged survival in an orthotopic murine glioma model. Moreover, combination therapy led to an increase in the proportion of probiotic bacteria in the mouse gut microbiota, resulting in elevated levels of antitumor metabolites and a decrease in metabolites that affect immune cell function.
    Keywords:  PD-1/PD-L1; PI3K/Akt signaling pathway; anti-tumor immunity; glioma; gut microbiota and metabolites; sodium butyrate
    DOI:  https://doi.org/10.3389/fimmu.2025.1532528
  8. J Neuroinflammation. 2025 May 01. 22(1): 129
    Gut microbiota and their influence in brain cancer milieu.
    Bandari BharathwajChetty, Aviral Kumar, Pranav Deevi, Mohamed Abbas, Athba Alqahtani, Liping Liang, Gautam Sethi, Le Liu, Ajaikumar B Kunnumakkara.
      Microbial communities are not simply remnants of the past but dynamic entities that continuously evolve under the selective pressures of nature, reflecting the intricate and adaptive processes of evolution. The microbiota residing in the various regions of the human body has numerous roles in different physiological processes such as nutrition, metabolism, immune regulation, etc. In the zeal of achieving empirical insights into the ambit of the gut microbiome, the research over the years led to the revelation of reciprocal interaction between the gut microbiome and the cognitive functioning of the human body. Dysbiosis in the gut microbial composition disturbs the homeostatic cognitive functioning of the human body. This dysbiosis has been associated with various chronic diseases, including brain cancer, such as glioma, glioblastoma, etc. This review explores the mechanistic role of dysbiosis-mediated progression of brain cancers and their subtypes. Moreover, it demonstrates the regulatory role of microbial metabolites produced by the gut microbiota, such as short-chain fatty acids, amino acids, lipids, etc., in the tumour progression. Further, we also provide valuable insights into the microbiota mediating the efficiency of therapeutic regimens, thereby leveraging gut microbiota as potential biomarkers and targets for improved treatment outcomes.
    Keywords:  Brain cancer; Glioblastoma; Glioma; Gut brain axis; Gut microbiome; Immune modulation; Metabolites; Probiotics; Tumour micro-environment
    DOI:  https://doi.org/10.1186/s12974-025-03434-2
  9. Neuro Oncol. 2025 Apr 30. pii: noaf112. [Epub ahead of print]
    The TCR Repertoire: A Window Into Pediatric Brain Tumor Immunity.
    Takahide Nejo, Robert M Prins, Hideho Okada.
      
    DOI:  https://doi.org/10.1093/neuonc/noaf112
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