bims-malgli Biomed News
on Biology of malignant gliomas
Issue of 2025–10–12
ten papers selected by
Oltea Sampetrean, Keio University
  1. Methylation-induced suppression of YAP/TAZ confers sensitivity to HDAC inhibitors in high grade IDH mutant gliomas.
  2. Now you see me; now you don't.
  3. Contralateral Neurofluid Dynamics Predict Survival in IDH Wild-type Glioblastoma: A DTI-ALPS and Free Water Imaging Study.
  4. A precision medicine umbrella trial to nominate promising therapies for glioblastoma.
  5. Immunopathology of Glioblastoma.
  6. How glioblastoma stem cells turn inflammatory cues into tumor growth and immune suppression.
  7. Dual molecular therapy targeting tumor cell heterogeneity improves therapeutic efficacy in glioblastoma.
  8. Harnessing ferroptosis to transform glioblastoma therapy and surmount treatment resistance.
  9. Screening for Tumor Microtube-Targeting Drugs Identifies PKC Modulators as Multipotent Inhibitors of Glioblastoma Progression.
  10. The promise of immunotherapy for central nervous system tumours.
  1. JCI Insight. 2025 Oct 09. pii: e195385. [Epub ahead of print]
    Methylation-induced suppression of YAP/TAZ confers sensitivity to HDAC inhibitors in high grade IDH mutant gliomas.
    Thomas K Sears, Matthew McCord, Wenxia Wang, Alicia Steffens, Kathleen McCortney, Rahul Chaliparambil, Jann N Sarkaria, Craig M Horbinski.
      IDH1/2 mutations (IDHmut) increase methylation of DNA and histones in gliomas. IDHmut inhibitors are effective against low-grade IDHmut gliomas, but new strategies against high grade IDHmut gliomas are needed. Although histone deacetylase inhibitors (HDACi) are ineffective against IDHwt glioblastoma (GBM), their potential in IDHmut gliomas has not been extensively studied. We previously established that IDHmut gliomas are more sensitive to HDACi than IDHwt GBM. Here we show that IDHmut is associated with greater sensitivity to HDACi only in glioma, not in IDHmut chondrosarcoma or cholangiocarcinoma. While HDACi induced more histone acetylation and gene regulation in IDHmut glioma than in IDHwt GBM, such acetylation was mostly within gene deserts, whereas IDHmut glioma promoters paradoxically lost histone acetylation. Two mediators of HDACi resistance, YAP and TAZ, were methylated and suppressed in IDHmut gliomas, but not in other IDHmut cancers. Inducing YAP or TAZ expression in IDHmut gliomas conferred resistance to HDACi. Finally, belinostat extended in vivo survival only in IDHmut glioma models, not in IDHmut GBM models. Our findings provide a mechanistic rationale for further studies of HDACi in IDHmut glioma patients, as well as the potential use of YAP/TAZ as a biomarker of HDACi sensitivity in cancers.
    Keywords:  Biomarkers; Brain cancer; Cell biology; Molecular pathology; Oncology
    DOI:  https://doi.org/10.1172/jci.insight.195385
  2. Sci Transl Med. 2025 Oct 08. 17(819): eadz1286
    Now you see me; now you don't.
    Pedro R Lowenstein.
      Multiomics on serial glioblastoma biopsies can enable differentiation of pseudoprogression from true tumor progression (see Ling et al.).
    DOI:  https://doi.org/10.1126/scitranslmed.adz1286
  3. Neuro Oncol. 2025 Oct 11. pii: noaf242. [Epub ahead of print]
    Contralateral Neurofluid Dynamics Predict Survival in IDH Wild-type Glioblastoma: A DTI-ALPS and Free Water Imaging Study.
    Akifumi Hagiwara, Wataru Uchida, Takuya Ozawa, Kaito Takabayashi, Rui Zou, Benjamin M Ellingson, Christina Andica, Junko Kikuta, Toshiaki Akashi, Akihiko Wada, Kanako Kunishima Kumamaru, Koji Kamagata, Osamu Akiyama, Akihide Kondo, Shigeki Aoki.
       BACKGROUND: Glioblastoma (GBM) may disrupt glymphatic function and neurofluid dynamics locally and in distant brain regions. However, the prognostic relevance of such alterations remains unclear. We investigated whether diffusion tensor image analysis along the perivascular space (DTI-ALPS) and free water (FW) imaging serve as biomarkers of glymphatic dysfunction and survival in patients with IDH wild-type GBM.
    METHODS: We retrospectively analyzed preoperative MRI data from 277 patients in the UPENN-GBM and 269 patients in the UCSF-PDGM cohorts. The ALPS index and FW volume fraction were quantified in tumor regions and normal-appearing white matter (NAWM) in both hemispheres. Data harmonization was performed using ComBat to adjust for intersite variability. Survival analyses were conducted using log-rank tests and Cox regression models. Optimal ALPS index and FW thresholds were derived from the UPENN-GBM dataset and validated in the UCSF-PDGM.
    RESULTS: The ALPS index was significantly lower in tumor regions than NAWM (P < .01). In the contralateral hemisphere, a lower ALPS index and higher FW in NAWM were independently associated with shorter overall survival (HR = 0.75, P = .027 for ALPS index; HR = 1.34, P = .04 for FW). The identified thresholds successfully stratified survival in UPENN-GBM and were validated in UCSF-PDGM (P = .011 for ALPS; P = .038 for FW).
    CONCLUSIONS: Neurofluid dynamic alterations in the contralateral hemisphere, assessed using DTI-ALPS and FW imaging, were independently associated with survival in patients with IDH wild-type GBM. These findings support the use of glymphatic imaging markers for prognostic stratification and therapeutic targeting.
    Keywords:  DTI-ALPS; Free water imaging; Glioblastoma; Glymphatic system; Neurofluid
    DOI:  https://doi.org/10.1093/neuonc/noaf242
  4. Neuro Oncol. 2025 Oct 10. pii: noaf243. [Epub ahead of print]
    A precision medicine umbrella trial to nominate promising therapies for glioblastoma.
    Jann N Sarkaria, William H Donner.
      
    DOI:  https://doi.org/10.1093/neuonc/noaf243
  5. Annu Rev Pathol. 2025 Oct 08.
    Immunopathology of Glioblastoma.
    Jiabo Li, James L Ross, Dolores Hambardzumyan, Daniel J Brat.
      Glioblastoma (GBM), the most frequent and malignant primary brain tumor, is characterized by a highly diverse and profoundly immunosuppressive tumor microenvironment (TME) that provides an unconstrained environment for tumor progression and significantly complicates therapeutic interventions. Despite advances in immunotherapeutic approaches, such as chimeric antigen receptor T cell and immune checkpoint inhibitors, efficacy remains limited due to the complexity of the GBM TME and robust immune evasion mechanisms. In this review, we elucidate the intricate interplay among cellular components within the TME that lead to this immunosuppressive state, including tumor-associated macrophages/microglia, myeloid-derived suppressor cells, regulatory T cells, and glioma stem cells, as well as other critical elements that contribute to TME complexity, such as the severe hypoxia associated with central necrosis, the blood-brain barrier, and the extracellular matrix. This review also highlights mechanisms of immune evasion and recent immunotherapeutic approaches along with their biologic rationale, underscoring the need for integrated therapeutic strategies that both target immunosuppressive elements and enhance immune activation.
    DOI:  https://doi.org/10.1146/annurev-pathmechdis-042524-025950
  6. Dev Cell. 2025 Oct 06. pii: S1534-5807(25)00366-1. [Epub ahead of print]60(19): 2535-2537
    How glioblastoma stem cells turn inflammatory cues into tumor growth and immune suppression.
    Wenhui Chen, Yanjie Shen, Guangshuai Jia.
      Chronic inflammation shapes the tumor microenvironment and influences cancer stem cell behavior. In this issue of Developmental Cell, Gu et al. identify TNFAIP6 as a key responder to tumor necrosis factor alpha (TNF-α) that promotes self-renewal of glioblastoma stem cells and reprograms pro-inflammatory macrophages toward an immunosuppressive phenotype, identifying a therapeutic vulnerability in glioblastoma.
    DOI:  https://doi.org/10.1016/j.devcel.2025.06.011
  7. iScience. 2025 Sep 19. 28(9): 113456
    Dual molecular therapy targeting tumor cell heterogeneity improves therapeutic efficacy in glioblastoma.
    Shuichiro Hirano, Atsuhito Uneda, Yoshihiro Otani, Yasuki Suruga, Ryoji Imoto, Madoka Hokama, Tsuyoshi Umeda, Ryosuke Ikemachi, Shohei Nishigaki, Nobushige Tsuboi, Keigo Makino, Naoya Kemmotsu, Yasuhito Kegoya, Yuji Matsumoto, Yusuke Tomita, Yosuke Shimazu, Joji Ishida, Kentaro Fujii, Hiroaki Wakimoto, Shota Tanaka, Isao Date.
      The intratumoral heterogeneity of glioblastoma, comprising glioblastoma stem cells (GSCs) and differentiated glioblastoma cells (DGCs), contributes to treatment resistance. We explored combination therapy targeting both GSCs and DGCs. Candidate drugs predicted to be highly effective against GSCs and DGCs were identified through in silico screening, which utilized antitumor efficacy data of therapeutic agents and gene expression profiles of cancer cell lines. IC50 values of the candidate drugs were determined using in vitro cell proliferation assays. Belinostat and Dasatinib were found to be the most effective against GSCs and DGCs, respectively. Their combination showed synergistic effects in vitro. Transcriptome analysis revealed the suppression of the G2/M transition and the PI3K-Akt-mTOR signaling pathway following combination therapy. Histological analysis confirmed reduced proliferation and increased apoptosis. In silico screening successfully identified candidate drugs for GSCs and DGCs. These results suggest that the dual targeting of GSCs and DGCs may help overcome intratumoral heterogeneity in glioblastoma.
    Keywords:  Biological sciences; Cancer; Natural sciences; Pharmacology
    DOI:  https://doi.org/10.1016/j.isci.2025.113456
  8. Cell Death Discov. 2025 Oct 07. 11(1): 448
    Harnessing ferroptosis to transform glioblastoma therapy and surmount treatment resistance.
    Shilpi Singh, Iteeshree Mohapatra, Debashis Barik, Haoyi Zheng, Stefan Kim, Mayur Sharma, Clark C Chen, Gatikrushna Singh.
      Glioblastoma remains the most aggressive and treatment-resistant brain malignancy, driven by genetic heterogeneity, metabolic plasticity, and an immunosuppressive tumor microenvironment (TME). Current therapies rely on inducing tumor cell death through DNA damage; however, glioma stem cells (GSCs) upregulate compensatory DNA repair pathways, promoting resistance and tumor recurrence. Ferroptosis, an iron-dependent form of regulated cell death driven by lipid peroxidation, offers a novel therapeutic strategy to overcome therapy resistance by exploiting glioblastoma's metabolic vulnerabilities. Unlike conventional therapies, ferroptosis bypasses DNA repair mechanisms, making it particularly effective against therapy-resistant GSCs. It reduces tumor growth by triggering iron-catalyzed oxidative stress, disrupting lipid metabolism, and pushing glioblastoma cells beyond their oxidative threshold. However, resistance mechanisms to ferroptosis, including iron metabolism regulators (IREB2 and ferritinophagy), lipid peroxidation enzymes (ACSL4 and ALOXs), and protective pathways (cystine transporters and glutathione peroxidase 4), limit its therapeutic potential. Extracellular vesicle-mediated iron transfer further contributes to ferroptosis resistance, fostering chemoresistance and radio-resistance. Beyond direct tumor killing, ferroptosis modulates the TME by releasing damage-associated molecular patterns, inducing reactive oxygen species, stimulating CD8+ T-cell activation, enhancing immune checkpoint blockade efficacy, and reprogramming tumor-associated macrophages toward an anti-tumor phenotype. Ferroptosis-based strategies, including glutathione peroxidase 4 inhibitors, nanoparticle-mediated iron delivery, and RNA-based therapies, offer promising avenues for enhancing glioblastoma treatment efficacy. This review highlights ferroptosis as a promising strategy for overcoming glioblastoma resistance by integrating it with chemotherapy, radiotherapy, and immunotherapy to enhance treatment efficacy. Given the complexity of glioblastoma, personalized ferroptosis-based approaches that address tumor heterogeneity, immune interactions, and metabolic adaptations are crucial for overcoming therapy resistance. Refining ferroptosis-targeted strategies by incorporating metabolic, immune, and genetic considerations can lead to more durable and effective therapies, ultimately transforming glioblastoma treatment and improving patient outcomes.
    DOI:  https://doi.org/10.1038/s41420-025-02744-x
  9. Cancer Discov. 2025 Oct 09.
    Screening for Tumor Microtube-Targeting Drugs Identifies PKC Modulators as Multipotent Inhibitors of Glioblastoma Progression.
    Daniel D Azorín, Dirk C Hoffmann, Nils R Hebach, Erik Jung, David Hausmann, Miriam Ratliff, Ling Hai, Sandra Horschitz, Ammar Jabali, Matthias Osswald, Matthia A Karreman, Tobias Kessler, Susann Wendler, Chanté D Mayer, Cathrin Löb, Pascal Lehnert, Gina Cebulla, Denise Reibold, Rajiv K Khajuria, Pino Bordignon, Andreas E Moor, Tim Holland-Letz, Jill Reckless, Nigel Ramsden, David Grainger, Anna Kreshuk, Philipp Koch, Wolfgang Wick, Sophie Heuer, Frank Winkler.
      Glioblastomas are incurable primary brain tumors that depend on neural-like cellular processes, tumor microtubes (TMs), to invade the brain. TMs also interconnect single tumor cells to a communicating multicellular network that resists current therapies. Here, we developed a combined, comprehensive in vitro/in vivo anti-TM drug screening approach, including machine-learning-based analysis tools. Two Protein Kinase C (PKC) modulators robustly inhibited TM formation and pacemaker tumor cell-driven, TM-mediated glioblastoma cell network communication. Since TM-unconnected tumor cells exhibited increased sensitivity to cytotoxic therapy, the PKC activator TPPB was combined with radiotherapy, and long-term intravital 2-photon microscopy paired with spatially resolved multiomics revealed anti-TM and anti-tumor effects. TPPB treatment also decreased the expression of tweety family member 1 (TTYH1), a key driver of invasive TMs. Our study establishes a novel screening pipeline for anti-TM drug development, identifies a TM master regulator pathway, and supports the approach of TM targeting for efficient brain tumor therapies.
    DOI:  https://doi.org/10.1158/2159-8290.CD-24-0414
  10. Nat Rev Immunol. 2025 Oct 06.
    The promise of immunotherapy for central nervous system tumours.
    Jasia Mahdi, Vrunda Trivedi, Michelle Monje.
      The nervous and immune systems are intricately linked to one another through bi-directional crosstalk. Given the limited therapeutic options for aggressive and refractory central nervous system (CNS) tumours, immunotherapies are increasingly being explored as potential treatments for these malignancies. In this Review, we provide an overview of the nervous system-immune system connections that provide the basis for the use of immunotherapy to treat CNS tumours. We then summarize the outcomes from preclinical and clinical studies that have used immunotherapies, including chimeric antigen receptor T cell therapy, oncolytic viruses, cancer vaccines and immune-checkpoint inhibitors, for the treatment of primary CNS cancers such as high-grade gliomas, refractory embryonal brain tumours and primary CNS lymphomas. Finally, we review the neurological symptoms and syndromes that can arise with these immunotherapeutic approaches.
    DOI:  https://doi.org/10.1038/s41577-025-01227-5
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