bims-malgli Biomed News
on Biology of malignant gliomas
Issue of 2025–08–31
twelve papers selected by
Oltea Sampetrean, Keio University



  1. Acta Neuropathol Commun. 2025 Aug 21. 13(1): 181
      Endothelial transdifferentiation represents a multifaceted process wherein glioma stem cells (GSCs) gradually adopt endothelial characteristics, marked by the expression of endothelial markers (CD31, CD34) and functional traits, while concurrently relinquishing their stem-like properties. This phenomenon is heterogenous in glioblastoma (GBM) samples, but holds importance in terms of prognosis. Typically occurring within hypoxic environments, particularly in perinecrotic regions, endothelial transdifferentiation is influenced by the secretome of neighboring cells, which orchestrates the activation of various signaling pathways including Notch during endothelial lineage commitment, PI3K/AKT, Wnt/β-catenin and epithelial-mesenchymal transition (EMT) during both commitment and maturation. Initially, GSCs organize into vascular-like channels resembling vasculogenic mimicry and express CD144; however, this signature diminishes as endothelial maturation progresses. GSC-derived endothelial cells (ECs) eventually integrate with normal ECs from the tumor periphery, yielding a mosaic pattern. Endothelial transdifferentiation plays a role in response to standard treatments such as temozolomide chemotherapy and radiotherapy.
    Keywords:  Endothelial cells; Glioma stem cells; Transdifferentiation; Vasculogenic mimicry
    DOI:  https://doi.org/10.1186/s40478-025-02031-x
  2. JCI Insight. 2025 Aug 22. pii: e181903. [Epub ahead of print]10(16):
      While the accumulation of tumor-associated macrophages (TAMs) in glioblastoma (GBM) has been well documented, targeting TAMs has thus far yielded limited clinical success in slowing GBM progression due, in part, to an incomplete understanding of TAM function. Using an engineered 3D hydrogel-based model of the brain tumor microenvironment (TME), we show that M2-polarized macrophages stimulate transcriptional and phenotypic changes in GBM stem cells (GSCs) closely associated with the highly aggressive and invasive mesenchymal subtype. By combining proteomics with GBM patient single-cell transcriptomics, we identify multiple TAM-secreted proteins with putative proinvasive functions and validate TGF-β induced (TGFBI, also known as BIGH3) as a targetable TAM-secreted tumorigenic factor. Our work highlights the utility of coupling multiomics analyses with engineered TME models to investigate TAM-cancer cell crosstalk and offers insights into TAM function to guide TAM-targeting therapies.
    Keywords:  Brain cancer; Extracellular matrix; Immunology; Macrophages; Oncology
    DOI:  https://doi.org/10.1172/jci.insight.181903
  3. Neuro Oncol. 2025 Aug 16. pii: noaf178. [Epub ahead of print]
       BACKGROUND: Extracranial metastases from adult gliomas cause diagnostic and therapeutic challenges and are generally poorly investigated. The aim of this study was to provide clinical and molecular insights into glioma metastasis.
    METHODS: Our cohort consisted of tumor tissue from 16 glioma patients with metastasis (14 glioblastomas and 2 lower-grade gliomas). Paired primary tumors, recurrences, and metastases were investigated by DNA sequencing, genome-wide DNA methylation profiling, RNA sequencing, immunohistochemistry, and MRI examinations.
    RESULTS: The metastases were distributed across scalp/upper neck (8), lymph nodes (5), bone (2), and liver (1). Six out of 14 glioblastomas displayed significant sarcomatous differentiation, consistent with the otherwise rare histological subtype gliosarcoma. A majority of the scalp lesions were connected to the intracranial brain tumor via tumor extension through craniotomy burr holes, proposing that surgery is a contributing factor to tumor spread. Next-generation sequencing-based mutational analysis revealed that the true metastases originated from the primary tumors and not later recurrences. We observed tumor plasticity as the tumors progressed to metastasis, demonstrated by changes in epigenetic methylation classes and transcriptional subtypes. Despite different locations of metastases in the cohort, the immune cell composition in the tumor microenvironment remained overall stable during tumor progression.
    CONCLUSION: Metastases from adult gliomas originates from the primary brain tumors and not later recurrences. While RNA sequencing and methylation profiling revealed tumor plasticity during progression to metastasis, the immune cell composition remained overall stable.
    Keywords:  Glioblastoma; TME; glioma; gliosarcoma; metastasis
    DOI:  https://doi.org/10.1093/neuonc/noaf178
  4. Acta Neuropathol Commun. 2025 Aug 23. 13(1): 183
      H3K27-altered diffuse midline glioma (DMG) is a fatal disease, including four subtypes H3.3-mutant, H3.1/H3.2-mutant, H3-wildtype with EZHIP overexpression, and EGFR-mutant. H3F3B, another gene encoding histone H3.3 in addition to H3F3A, was ever reported to be mutated in DMGs. However, the clinical and molecular characteristics of H3F3B-mutant DMGs is yet understood. The clinical and radiological information of 9 patients with H3F3B-mutant DMG were retrospectively collected. Tumor specimens underwent DNA methylation profiling and next-generation sequencing. All tumors harbored somatic H3F3B p.K27I mutation. Average patient age was 46 ± 6.86 years, 6 tumors located in spinal cord, 5 tumors involved brainstem and 2 arose in the thalamus. Immunohistochemistry showed these tumors exhibited completely or mosaic-like loss of H3K27me3 expression. Unsupervised t-distributed stochastic neighbor embedding (t-SNE) analysis of DNA methylation profiles showed that H3F3B-mutant DMGs formed a unique methylation cluster separate from other gliomas with H3K27me3 loss and DMGs with canonical histone H3 mutation. PPM1D and NF1 were frequently mutated in H3F3B-mutant DMGs. Survival analysis showed that H3F3B-mutant DMGs had poor prognosis comparable to H3K27M-mutant DMGs. Taken together, H3F3B mutation also cause a loss of H3K27 trimethylation in DMGs and result in poor prognosis. The distinct characteristics of DNA methylation and mutational spectrum between H3F3B-mutant DMGs and canonical H3K27M-mutant DMGs might suggest divergent underlying mechanism of gliomagenesis.
    Keywords:  DNA mutation; Diffuse midline glioma; H3F3B; Histone H3; Methylation
    DOI:  https://doi.org/10.1186/s40478-025-02101-0
  5. Brain Sci. 2025 Aug 19. pii: 884. [Epub ahead of print]15(8):
      Glioblastoma (GBM) is the most aggressive primary brain tumor, characterized by rapid proliferation, invasiveness, therapeutic resistance, and an immunosuppressive tumor microenvironment. A subpopulation of glial stem-like cells (GSCs) within GBM tumors contributes significantly to tumor initiation, progression, and relapse, displaying remarkable adaptability to oxidative stress and metabolic reprogramming. Recent evidence implicates the atypical kinases RIOK1 and RIOK2 in promoting GBM growth and proliferation through their interaction with oncogenic pathways such as AKT and c-Myc. Concurrently, the redox-sensitive Nrf2/Keap1 axis regulates antioxidant defenses and supports GSC survival and chemoresistance. Additionally, aberrant activation of the canonical Wnt/β-catenin pathway in GSCs enhances their self-renewal, immune evasion, and resistance to standard therapies, particularly under oxidative stress conditions. This review integrates current knowledge on how redox homeostasis and key signaling pathways converge to sustain GSC maintenance and GBM malignancy. Finally, we discuss emerging redox-based therapeutic strategies designed to target GSC resilience, modulate the tumor immune microenvironment, and surmount treatment resistance.
    Keywords:  cancer stem cells; glial stem-like cells; glioblastoma; glioma; oxidative stress; redox-targeted therapy
    DOI:  https://doi.org/10.3390/brainsci15080884
  6. J Drug Target. 2025 Aug 27. 1-11
      Glioblastoma is a devastating disease with a high mortality rate. Gene therapy with anti-microRNA inhibitors has been suggested as a new modality for treatment of glioblastoma. In this study, glioblastoma-targeted extracellular vesicles (EVs) were produced with specific ligands and evaluated as a carrier of anti-microRNA-21 oligonucleotides (AMO21). Angiopep-2 (ANG) and chlorotoxin (CTX) were linked to EVs by DNA recombination techniques. Cholesterol-conjugated AMO21 (AMO21c) was loaded onto the EVs decorated with ANG or CTX (ANG-EV or CTX-EV) by hydrophobic interactions. In vitro cellular uptake assays indicated that CTX-EV had higher delivery efficiency than unmodified EV (Unmod-EV) and ANG-EV. In addition, CTX-EV had higher transcytosis efficiency than the other EVs, suggesting that it effectively passes through the blood-brain barrier. In orthotopic glioblastoma animal models, CTX-EV delivered AMO21c more efficiently than Lipofectamine/AMO21c, Unmod-EV/AMO21c and ANG-EV/AMO21c. As a result, a greater decrease in tumour size with CTX-EV/AMO21c was observed, as compared with Lipofectamine/AMO21c, Unmod-EV/AMO21c and ANG-EV/AMO21c. CTX-EV/AMO21c induced the expression of the phosphatase and tensin homolog (PTEN) and programmed cell death 4 (PDCD4) genes in tumours. In addition, apoptosis levels in tumour tissues were enhanced by CTX-EV/AMO21c, as compared with the other samples. In conclusion, CTX-EV is effective for targeted delivery of AMO21 to glioblastoma and may have potential in glioblastoma gene therapy.
    Keywords:  Glioblastoma; angiopep-2; anti-microRNA oligonucleotide; chlorotoxin; extracellular vesicles
    DOI:  https://doi.org/10.1080/1061186X.2025.2550594
  7. Cancer Res Commun. 2025 Aug 22.
      Glioblastoma (GBM) tumors remain a challenge for immunotherapy owing to their heterogeneous and immunologically cold properties. GBM cells change the composition of the neural extracellular matrix (ECM), affecting the mobility, survival, and function of immune cells such as tumor-associated microglia and infiltrated macrophages (TAMs). The ECM protein EFEMP1/fibulin-3 is a pericellular component uniquely upregulated in GBM compared to normal brain, which promotes tumor growth and invasion. Here, we demonstrate that fibulin-3 indirectly modulates TAM behavior and can be targeted to restore innate immune responses. Intracranial tumors initiated by fibulin-3-deficient GBM cells showed increased presence of TAMs with decreased immunosuppression markers (Arginase, CD206), whereas the opposite effects were observed in tumors overexpressing fibulin-3. In silico analyses revealed a positive correlation between fibulin-3 and an immunosuppressive signature that was validated in GBM stem cells (GSCs) and in vivo. We further demonstrated that fibulin-3 regulates the expression of immunosuppressive signals (CSF-1, TGF-β1, and CD47) by autocrine activation of NF-κB signaling. Immunosuppressive signals were downregulated by knockdown of fibulin-3 in GSCs and by inhibition of this protein using an anti-fibulin-3 antibody. Myeloid cells exhibited higher phagocytic activity and killing of GBM cells in presence of this antibody. Furthermore, locoregional delivery of anti-fibulin-3 in mice with intracranial GBM increased the presence of pro-inflammatory TAMs, thereby reducing tumor viability. Our findings show that anti-fibulin-3 approaches, which affect the ECM surrounding tumor and immune cells, can diminish immunosuppression in GBM and boost innate immune responses against the tumor.
    DOI:  https://doi.org/10.1158/2767-9764.CRC-25-0083
  8. Comput Biol Med. 2025 Aug 21. pii: S0010-4825(25)01261-2. [Epub ahead of print]196(Pt C): 110909
      Recent biological research has highlighted the relevance of myeloid-cell populations in glioma growth, with a particular role played by tumor-associated macrophages (TAMs), which comprise resident microglia and monocyte-derived macrophages. Additionally, radiation therapy, the most common treatment for gliomas, significantly alters the tumor microenvironment, affecting TAMs and contributing to tumor recurrence. Promising preclinical studies have identified and developed drugs targeting TAMs. The development and combined deployment of these therapies require in silico techniques that enable us to optimize their outcomes. To do so, we need mathematical models of glioma growth and therapy response that explicitly incorporate TAMs-an often overlooked component in existing models. Here, we present a dynamical model of glioma growth driven by tumor-immune interactions. The model was parametrized using published data from mice experiments, including responses to ionizing radiation. We used this model to investigate glioma progression under radiotherapy combined with three treatments targeting distinct aspects of TAM biology. Simulations revealed that anti-CD47 enhanced the otherwise weak phagocytic activity, extending the upper tail of the survival curve. α-CD49d, which limits monocyte trafficking after irradiation, offered consistent survival benefits across digital twins of mice. Finally, CSF-1R inhibitors, which block the primary growth factor regulating TAM function, resulted in the largest overall survival improvement in silico. Our results aligned well with experimental evidence, suggesting that the model may help inform the optimization of myeloid cell-targeted immunotherapies, including their timing, dosage, and combination with radiation therapy, with potential relevance for improving glioma treatment strategies.
    Keywords:  Glioma; Immunotherapy; Macrophages; Mathematical model; Myeloid cells; Radiation; TAMs
    DOI:  https://doi.org/10.1016/j.compbiomed.2025.110909
  9. Nat Med. 2025 Aug 21.
      Mutant isocitrate dehydrogenase (mIDH) inhibition significantly improves progression-free survival in patients with mIDH WHO grade 2 glioma; however, a large proportion of patients will progress, and mechanisms of adaptation to mIDH inhibition remain poorly understood. Perioperative studies with evaluation of paired pre- and post-treatment samples enable detailed understanding of drug response, facilitating biomarker development, but are rare in glioma owing to safety and cost concerns. Here we conducted a single-arm, open-label feasibility perioperative trial in patients with mIDH1 low-grade glioma, treatment naive to radiation and chemotherapy, with safusidenib (AB-218/DS-1001b), an orally available small-molecule inhibitor of mIDH1. As of 8 November 2024, 10 patients were enrolled and have completed the perioperative component, with a median follow-up of 14 months. Patients continue postoperative safusidenib with ongoing follow-up for safety and efficacy. The primary endpoint showed the feasibility and acceptability of conducting a two-stage perioperative trial. One patient experienced a serious surgery-related adverse event, and ten reported safusidenib-related adverse events; most were grade 1, and one experienced grade 3 elevation of transaminases. Tumor 2-hydroxyglutarate quantification revealed on-target activity, associated with alterations in differentiation programs and neural excitability, functionally validated in post hoc analysis by patch-clamp electrophysiology. Taken together, these results provide a detailed investigation of observations associated with mIDH inhibition in glioma. The study shows the safety and feasibility of this perioperative approach, which can be applied broadly in clinical trial design, serving as proof of concept for advancing drug development in glioma. ClinicalTrials.gov registration: NCT05577416 .
    DOI:  https://doi.org/10.1038/s41591-025-03884-4
  10. Sci Rep. 2025 Aug 26. 15(1): 31344
      Glioblastomas are the most prevalent and malignant primary cancers in the brain. Given the promising prospects of immunotherapeutic approaches, there is increasing interest in obtaining precise knowledge of the immunologic status of the tumour microenvironment for each individual. We explored the feasibility of inferring this tumour immune component in a minimally invasive manner prior to any clinical intervention, taking advantage of the preoperative immune cell counts that can be easily obtained from the clinical records of the patients. The neutrophil-to-lymphocyte ratio (NLR) is the most extensive measure calculated from complete counts of peripheral blood. Despite there was an increase in the NLR in high grade tumours of our cohorts of study, we did not find evidence of any correlation between the NLR and different degrees of tumour immune infiltration in glioblastoma. The same negative result was obtained with the monocyte-to-lymphocyte ratio (MLR). In addition, glioblastomas associated with extreme values of peripheral NLR did not exhibit substantial gene expression differences that could be linked to distinct tumourigenic properties. Overall, these results suggest that peripheral immune cell ratios cannot be used to reliably infer the immune microenvironment within the tumour, underscoring the complexity of using peripheral markers to assess local tumour immunity.
    Keywords:  Blood; Glioma; MLR; Macrophage; Microenvironment; NLR; Neutrophil
    DOI:  https://doi.org/10.1038/s41598-025-16260-6
  11. Nat Commun. 2025 Aug 25. 16(1): 7279
      Tumor-infiltrating lymphocyte (TIL)-therapy has received FDA approval for the treatment of advanced melanoma and shows potential for broader applications in solid tumors, including glioblastoma. In this study, tumor-reactive TILs (tr-TILs) are isolated and enriched for CD137 expression from cavitron ultrasonic aspirator (CUSA) emulsions of 161 adult patients diagnosed with diffuse gliomas. Tr-TILs are successfully expanded in 87 out of the 161 patients, reflecting an expansion rate of 54%. Notably, the presence of IDH1 mutation and the cumulative dose of steroids are identified as significant negative predictors of expansion efficacy. The expanded tr-TILs exhibit distinct phenotypic and molecular dysfunctional features yet show upregulated expression of progenitor/memory-like markers and polyclonal T-cell receptors. Importantly, these tr-TILs demonstrate specific antitumor reactivity against autologous tumor cells in both in vitro and in vivo xenograft models. These findings provide a compelling background for a personalized immunotherapeutic approach while tackling one of the most significant challenges in oncology.
    DOI:  https://doi.org/10.1038/s41467-025-62263-2
  12. Nature. 2025 Aug 20.
      Glioblastoma (GBM) is an aggressive and highly therapy-resistant brain tumour1,2. Although advanced disease has been intensely investigated, the mechanisms that underpin the earlier, likely more tractable, stages of GBM development remain poorly understood. Here we identify axonal injury as a key driver of GBM progression, which we find is induced in white matter by early tumour cells preferentially expanding in this region. Mechanistically, axonal injury promotes gliomagenesis by triggering Wallerian degeneration, a targetable active programme of axonal death3, which we show increases neuroinflammation and tumour proliferation. Inactivation of SARM1, the key enzyme activated in response to injury that mediates Wallerian degeneration4, was sufficient to break this tumour-promoting feedforward loop, leading to the development of less advanced terminal tumours and prolonged survival in mice. Thus, targeting the tumour-induced injury microenvironment may supress progression from latent to advanced disease, thereby providing a potential strategy for GBM interception and control.
    DOI:  https://doi.org/10.1038/s41586-025-09411-2