bims-malgli Biomed News
on Biology of malignant gliomas
Issue of 2025–11–09
six papers selected by
Oltea Sampetrean, Keio University
  1. Olig1/2 Orchestrates Progenitor Cell Fates during Mammalian Cortical Gliogenesis and Gliomagenesis.
  2. cGAS-agonistic spherical nucleic acids reprogram the glioblastoma immune microenvironment and promote antitumor immunity.
  3. EZHIP boosts neuronal-like synaptic gene programs and depresses polyamine metabolism.
  4. Diffusely metastatic glioblastoma with FGFR3::TACC3 fusion: cell-free DNA fragmentation analyses and molecular characterization of matched primary and metastatic tumor sites.
  5. Injectable bioresorbable conductive hydrogels for multimodal brain tumor electroimmunotherapy.
  6. Reflecting on Scientific Growth and Innovation as the Society for Neuro-Oncology Turns 30.
  1. Nat Commun. 2025 Nov 05. 16(1): 9779
    Olig1/2 Orchestrates Progenitor Cell Fates during Mammalian Cortical Gliogenesis and Gliomagenesis.
    Yu Tian, Ziwu Wang, Feihong Yang, Wen Zhang, Jialin Li, Lin Yang, Tongye Fu, Wenhui Zheng, Zhejun Xu, Tong Ma, Yan You, Xiaosu Li, Jiangang Song, Yunli Xie, Zhengang Yang, Zhuangzhi Zhang.
      During cortical gliogenesis, tri-potential intermediate progenitor cells (Tri-IPCs) differentiate into oligodendrocyte precursor cells (OPCs) or olfactory bulb interneuron intermediate progenitors (OBIN-IPCs) - a developmental program frequently co-opted in glioblastoma (GBM) to drive tumorigenesis. Here, we show that the transcription factors Olig1/2 coordinately regulate Tri-IPC fate specification through dual transcriptional mechanisms: they activate OPC specification while simultaneously repressing OBIN-IPC generation by directly suppressing Gsx2 expression. Genetic ablation of Olig1/2 redirects Tri-IPCs from producing proliferative OPCs to generating non-proliferative OBIN-IPCs, concomitant with Gsx2 upregulation. Mechanistically, Olig1/2 bind and silence multiple conserved enhancer elements of Gsx2. Remarkably, in proneural GBM models, Olig1/2 deletion reprograms glioma stem cells toward OBIN-IPC-like cells, potently inhibiting tumor growth and improving survival. Integrative multi-omics and immunohistochemical staining analyses further identify cortical Tri-IPCs as the likely cellular origin of human H3.3G34R/V gliomas. These findings establish Olig1/2 as master regulators linking normal gliogenesis to gliomagenesis, and reveal therapeutic opportunities through fate reprogramming of glioma cells.
    DOI:  https://doi.org/10.1038/s41467-025-64753-9
  2. Proc Natl Acad Sci U S A. 2025 Nov 11. 122(45): e2409557122
    cGAS-agonistic spherical nucleic acids reprogram the glioblastoma immune microenvironment and promote antitumor immunity.
    Akanksha S Mahajan, Corey Dussold, Seunghyun Kim, Rachel Jarvis, Lisa A Hurley, Serena Tommasini-Ghelfi, Jungsoo Park, Connor M Forsyth, Bin Zhang, Jason Miska, Amy B Heimberger, Chad A Mirkin, Alexander H Stegh.
      The cyclic GMP-AMP synthase-Stimulator of Interferon Genes (cGAS-STING) pathway is an important DNA-sensing mechanism that increases T cell trafficking and activation in tumors and reverses the immunosuppressive phenotype of myeloid cells. Therefore, direct STING targeting using synthetic cyclic dinucleotides (CDNs) is an attractive strategy for treating lymphocyte-depleted and myeloid cell-enriched tumors, such as glioblastoma (GBM). However, inadequate bioavailability and poor cellular accumulation limit the clinical development of CDNs, particularly for noninvasive administration strategies. Spherical nucleic acids (SNAs) have emerged as promising modular constructs for creating therapeutic lead compounds for many diseases, including different forms of cancer. Here, we report the development of cGAS-activating SNAs that consist of gold nanoparticle cores functionalized with a shell of densely packed interferon-stimulatory DNA oligonucleotides (ISD45-SNAs). These nanostructures bind to cGAS, the sensor of cytosolic dsDNA upstream of STING, promoting the catalytic production of endogenous CDNs and downstream STING activation more potently than clinically tested CDNs. When administered intranasally or intratumorally to poorly immunogenic syngeneic GBM mouse models, ISD45-SNAs inhibit tumor growth more effectively than CDNs and promote long-term animal subject survival through specific cGAS-STING pathway activation. ISD45-SNAs induce a proinflammatory immune microenvironment enriched with effector T cells and proinflammatory macrophages. When coadministered with immune checkpoint inhibitors (ICI), they abolish GBM tumor development and induce long-term antiglioma immunity. These studies establish ISD45-SNAs as an immune-stimulatory modality for triggering innate and adaptive immune responses and increasing ICI efficacy for GBM treatment.
    Keywords:  DNA therapeutics; cGAS–STING; glioblastoma; immunotherapy; tumor microenvironment
    DOI:  https://doi.org/10.1073/pnas.2409557122
  3. Acta Neuropathol Commun. 2025 Nov 07. 13(1): 227
    EZHIP boosts neuronal-like synaptic gene programs and depresses polyamine metabolism.
    Elham Hasheminasabgorji, Huey-Miin Chen, Taylor A Gatesman, Subhi Talal Younes, Gabrielle A Nobles, Farhang Jaryani, Heather Mao, Kwanha Yu, Benjamin Deneen, Wee Yong, Michael D Taylor, Sameer Agnihotri, Marco Gallo.
      It is currently understood that the characteristic loss of the repressive histone mark H3K27me3 in PFA ependymoma and diffuse midline glioma (DMG) are caused by complementary mechanisms mediated by EZHIP and the oncohistone H3K27M, respectively. To support the complementarity of these mechanisms, rare H3K27M-negative DMGs express EZHIP. Interestingly, EZHIP is one of the few genes recurrently mutated in PFA. The significance of EZHIP mutations in PFA, and whether EZHIP has wider functions in addition to repression of H3K27me3 deposition, are not known. Here, we investigated the mutational landscape of EZHIP in pediatric brain tumors. We found that EZHIP mutations occur not only in PFA, but also in rare medulloblastoma and pediatric high-grade glioma (HGG), including in H3K27-positive DMG. Contrary to current expectations, we show that mutant EZHIP is expressed in H3K27M-positive DMG. All the EZHIP-mutated HGG cases also have EGFR mutations. Further, we pursued better understanding of the function of EZHIP by expressing it in human-derived neural models. Our transcriptomic analyses indicate that EZHIP expression potentiates neuronal-like gene programs associated with synaptic function. Metabolomics data indicate that EZHIP leads to repression of methionine and polyamine metabolism, suggesting links between metabolic and epigenetic changes that are observed in PFA. Collectively, our results expand the repertoire of tumor types known to harbor EZHIP mutations and shed light on EZHIP-dependent metabolic and transcriptional programs in relevant neural models.
    DOI:  https://doi.org/10.1186/s40478-025-02141-6
  4. Acta Neuropathol Commun. 2025 Nov 03. 13(1): 221
    Diffusely metastatic glioblastoma with FGFR3::TACC3 fusion: cell-free DNA fragmentation analyses and molecular characterization of matched primary and metastatic tumor sites.
    Miguel A Hernandez-Rovira, Alicia Vagnozzi, Tyler Bales, Keerthana N Prabhu, Noushin Niknafs, Milan Chheda, Jiayi Huang, Albert H Kim, Michelle Miller-Thomas, Omar Butt, Katie D Vo, Bhargavi S Sovani, Ashwin Singh Parihar, Suzanne Crumley, Sonika Dahiya, Dimitrios Mathios.
      Extracranial metastasis of IDH-wildtype glioblastoma is very rare and poorly understood at the molecular level. We report a case of FGFR3::TACC3 fusion IDH-wildtype glioblastoma in a 61-year-old male, whose preoperative blood sample showed highly aberrant cfDNA fragmentation patterns, which could be suggestive of early systemic dissemination, undetected by standard-of-care imaging of his body. Eleven months post-resection and adjuvant therapy, he developed widespread extracranial metastases. Comprehensive molecular profiling of matched primary and metastatic tumors revealed broadly conserved genomic, transcriptomic, and copy number landscapes, with the metastasis harboring an additional ERCC6 deletion and enriched expression of receptor tyrosine kinase signaling genes. These findings provide rare insight into the genetic continuity and evolution underlying IDH-wildtype glioblastoma metastasis.
    Keywords:  FGFR3::TACC3; Fragmentation; Glioblastoma; Liquid biopsy; Metastasis; Systematic review; cfDNA
    DOI:  https://doi.org/10.1186/s40478-025-02142-5
  5. Nat Commun. 2025 Nov 03. 16(1): 9702
    Injectable bioresorbable conductive hydrogels for multimodal brain tumor electroimmunotherapy.
    Amit Singh Yadav, Umut Aydemir, Karin Hellman, Peter Ekström, Abdelrazek H Mousa, Jiaxin Li, Muhammad Anwar Shameem, Cedric Dicko, Johan Bengzon, Fredrik Ek, Martin Hjort, Roger Olsson.
      Current electrode technologies are too rigid for safe and effective delivery of electrotherapy in the brain, and patients with glioblastoma continue to face a devastating prognosis, with median survival stalled at 15 months despite intensive treatment with surgery, radiation, and chemotherapy. But these conventional approaches potentially compromise immune function, underscoring the urgent need for therapies that activate, rather than suppress, the immune system. Therefore, we introduce injectable conductive hydrogels engineered to match the softness of brain tissue while exhibiting electrical conductivities up to three orders of magnitude higher than any previously reported injectable hydrogels. They can be implanted through minimally invasive syringe capillaries as narrow as 30 µm-avoiding brain tissue damage-and via convection-enhanced delivery (CED) or endovascular catheters, the latter potentially eliminating the need for open brain surgery. Additionally, it can drape a resection cavity to eliminate residual tumor cells. In human glioblastoma tumors in the chicken chorioallantoic membrane model, implantation of the electrode using CED, followed by irreversible electroporation, obliterated tumors within three days. Other injection techniques impaired tumor growth, induced immunogenic cell death, and a robust infiltration of helper and cytotoxic T cells, alongside macrophages, highlighting the immune-activating and tumor-targeting capabilities.
    DOI:  https://doi.org/10.1038/s41467-025-65785-x
  6. Neuro Oncol. 2025 Nov 04. pii: noaf255. [Epub ahead of print]
    Reflecting on Scientific Growth and Innovation as the Society for Neuro-Oncology Turns 30.
    Macarena I De La Fuente, Priscilla K Brastianos, Bradley Gampel, Farshad Nassiri, David R Raleigh, Cristiane M Ida, Mohamed S Abdelbaki, Melike Pekmezci, Stephen Bagley, Jacob S Young, Rimas V Lukas, Angela C Hirbe, Benjamin M Ellingson, Javier Villanueva-Meyer, Anna Lasorella, Jann N Sarkaria, David H Gutmann, Daphne Haas-Kogan, Evanthia Galanis, Susan M Chang.
      The Society for Neuro-Oncology (SNO) marks its 30th anniversary in 2025, providing an opportunity to reflect on scientific advances and future directions on the field. Over three decades, SNO has catalyzed scientific innovation, education, mentorship, and global collaboration, advancing the care of patients with primary and metastatic brain tumors. Through its annual meeting and subspecialty conferences in pediatric neuro-oncology and brain metastases, as well as its journals, including Neuro-Oncology, Neuro-Oncology Practice, Neuro-Oncology Advances, and the recently launched Neuro-Oncology Pediatrics, SNO has established leading platforms for disseminating knowledge, sharing best practices, and shaping clinical, translational, and basic research worldwide. Scientific milestones during this period include the integration of molecular profiling into CNS tumor classification, advances in neuroimaging for diagnosis and treatment monitoring, targeted therapies for selected glioma patients and the evolution of brain metastases management from whole-brain radiotherapy to multimodal strategies that incorporate targeted and immune-based therapies. Pediatric neuro-oncology has similarly advanced with the use of histomolecular diagnostics, refined risk stratification, and the development of novel targeted agents, alongside an increased emphasis on survivorship. Looking forward, emerging insights into the tumor microenvironment and novel immunotherapeutic approaches offer promising directions for future discovery and translation.
    Keywords:  Brain metastases; Glioma; Pediatric Neuro-Oncology; Society of Neuro-Oncology (SNO)
    DOI:  https://doi.org/10.1093/neuonc/noaf255
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