bims-malgli Biomed News
on Biology of malignant gliomas
Issue of 2025–02–02
ten papers selected by
Oltea Sampetrean, Keio University
  1. Nanoparticle encapsulation enables systemic IGF-Trap delivery to inhibit intra-cerebral glioma growth.
  2. Laboratory-Engineered Glioblastoma Organoid Culture and Drug Screening.
  3. CircPRKD3-loaded exosomes concomitantly elicit tumor growth inhibition and glioblastoma microenvironment remodeling via inhibiting STAT3 signaling.
  4. Advancements in targeted and immunotherapy strategies for glioma: toward precision treatment.
  5. Extracellular Vesicles Released by Glioblastoma Cancer Cells Drive Tumor Invasiveness via Connexin-43 Gap Junctions.
  6. Therapeutic manipulation and bypass of the blood-brain barrier: powerful tools in glioma treatment.
  7. Oncolytic reprogramming of tumor microenvironment shapes CD4 T-cell memory via the IL6ra-Bcl6 axis for targeted control of glioblastoma.
  8. Corticosteroid-dependent association between prognostic peripheral blood cell-free DNA levels and neutrophil-mediated NETosis in patients with glioblastoma.
  9. Spatial distribution of immune cells and their proximity to STING+ cells are associated with survival in glioblastoma.
  10. Intestinal Bacteroides drives glioma progression by regulating CD8+ T cell tumor infiltration.
  1. Neuro Oncol. 2025 Jan 29. pii: noaf011. [Epub ahead of print]
    Nanoparticle encapsulation enables systemic IGF-Trap delivery to inhibit intra-cerebral glioma growth.
    Yinhsuan Michely Chen, Julien Chambon, Alexandre Moquin, Masakazu Hashimoto, Stephanie Perrino, Matthew Leibovitch, Yasmine Benslimane, Orçun Haçariz, Qin Yang, Ichiro Nakano, Brian Meehan, Janusz Rak, Stéphane Gagné, Pnina Brodt.
       BACKGROUND: Glioblastoma is an aggressive brain cancer with a 5-year survival rate of 5-10%. Current therapeutic options are limited, due in part to drug exclusion by the blood-brain barrier, restricting access of targeted drugs to the tumor. The receptor for the type 1 insulin-like growth factor (IGF-1R) was identified as a therapeutic target in glioblastoma. We previously reported that the intracerebral growth of glioma cells with reduced IGF-1R levels was inhibited. The objectives of this study were to evaluate the sensitivity of glioma cells to a novel IGF-axis inhibitor, the IGF-Trap, and optimize its delivery to the brain.
    METHODS: We tested the effect of the IGF-Trap on the growth of the human glioma stem cells MES-1123 and U87 MG cells, and of murine GL261 cells in vivo, using subcutaneous and orthotopic implantation.
    RESULTS: We show that the growth of glioma cells implanted subcutaneously or orthotopically in the brain was inhibited by systemic and direct intracerebral administration of IGF-Trap, respectively, resulting in increased survival. To increase the efficiency of systemic delivery to the brain, we encapsulated the IGF-Trap in trimethyl chitosan (TRIOZAN™) nanoparticles prior to intravenous injection. We found that nanoparticle encapsulation increased the uptake and retention of the IGF-Trap in the brain and resulted in an improved therapeutic effect against intra-cerebrally growing tumors.
    CONCLUSION: Our results identify the IGF-Trap as a potent inhibitor of intracerebral glioma growth and show that encapsulation in nanoparticles can improve delivery of biologics such as the IGF-Trap to the brain, thereby enhancing the therapeutic response.
    Keywords:  IGF-Trap; drug delivery; glioblastoma; nanoparticles; targeted therapy
    DOI:  https://doi.org/10.1093/neuonc/noaf011
  2. J Vis Exp. 2025 Jan 10.
    Laboratory-Engineered Glioblastoma Organoid Culture and Drug Screening.
    Changwen Wang, Nadja Stöffler, Hai-Kun Liu.
      Glioblastoma (GBM) is described as a group of highly malignant primary brain tumors and stands as one of the most lethal malignancies. The genetic and cellular characteristics of GBM have been a focal point of ongoing research, revealing that it is a group of heterogeneous diseases with variations in RNA expression, DNA methylation, or cellular composition. Despite the wealth of molecular data available, the lack of transferable pre-clinic models has limited the application of this information to disease classification rather than treatment stratification. Transferring the patients' genetic information into clinical benefits and bridging the gap between detailed descriptions of GBM, genotype-phenotype associations, and treatment advancements remain significant challenges. In this context, we present an advanced human GBM organoid model, the Laboratory Engineered Glioblastoma Organoid (LEGO), and illustrate its use in studying the genotype-phenotype dependencies and screening potential drugs for GBM. Utilizing this model, we have identified lipid metabolism dysregulation as a critical milestone in GBM progression and discovered that the microsomal triglyceride transfer protein inhibitor Lomitapide shows promise as a potential treatment for GBM.
    DOI:  https://doi.org/10.3791/67593
  3. Neuro Oncol. 2025 Jan 27. pii: noaf019. [Epub ahead of print]
    CircPRKD3-loaded exosomes concomitantly elicit tumor growth inhibition and glioblastoma microenvironment remodeling via inhibiting STAT3 signaling.
    Xiaoming Zhang, Mengyuan Jiang, Wanxiang Niu, Ben Xu, Ce Zhang, Minglong Yang, Shanshan Hu, Chaoshi Niu.
       BACKGROUND: Glioblastoma stem cells (GSCs) and their exosomes (exos) are involved in shaping the immune microenvironment, which is important for tumor invasion and recurrence. However, studies involving GSC-derived exosomal circular RNAs (GDE-circRNAs) in regulating tumor microenvironment (TME) remain unknown. Here, we comprehensively evaluated the significance of a novel immune-related GDE-circRNA in glioma microenvironment.
    METHODS: GDE-circPRKD3 was screened out through high-throughput sequencing and verified by RT-PCR, sanger sequencing and RNase R assays. A series of in vitro and in vivo experiments were performed to investigate the function of GDE-circPRKD3. RNA-seq, RNA immunoprecipitation, multicolor flow cytometry and western blotting were used to explore the regulation of GDE-circPRKD3 on STAT3 signaling-mediated TME remodeling.
    RESULTS: We have characterized a circRNA PRKD3 in GSC exosomes, and lower circPRKD3 expression predicts a worse prognosis for glioblastoma patients. Overexpression of GDE-circPRKD3 significantly impairs the biological competence of glioma and prolongs the survival of xenograft mice. GDE-circPRKD3 binds to HNRNPC in an m6A-dependent manner, accelerates mRNA decay of IL6ST and inhibits downstream target STAT3. Notably, GDE-circPRKD3 promotes CXCL10 secretion by reprogramming tumor-associated macrophages, which in turn recruits CD8+ tumor infiltrating lymphocytes against GBM. Moreover, brain-targeted lipid nanoparticle delivery of circPRKD3 combined with immune checkpoint blockade therapy achieves significant combinatorial benefits.
    CONCLUSION: This study provides a novel mechanism by which GDE-circPRKD3 relies on STAT3 signaling to remodel immunosuppressive TME and offers a potential RNA immunotherapy strategy for GBM treatment.
    Keywords:  STAT3; circPRKD3; exosome; glioma stem cell; tumor microenvironment
    DOI:  https://doi.org/10.1093/neuonc/noaf019
  4. Front Immunol. 2024 ;15 1537013
    Advancements in targeted and immunotherapy strategies for glioma: toward precision treatment.
    Guangyuan Gong, Lang Jiang, Jing Zhou, Yuanchao Su.
      In recent years, significant breakthroughs have been made in cancer therapy, particularly with the development of molecular targeted therapies and immunotherapies, owing to advances in tumor molecular biology and molecular immunology. High-grade gliomas (HGGs), characterized by their high malignancy, remain challenging to treat despite standard treatment regimens, including surgery, radiotherapy, chemotherapy, and tumor treating fields (TTF). These therapies provide limited efficacy, highlighting the need for novel treatment strategies. Molecular targeted therapies and immunotherapy have emerged as promising avenues for improving treatment outcomes in high-grade gliomas. This review explores the current status and recent advancements in targeted and immunotherapeutic approaches for high-grade gliomas.
    Keywords:  high-grade glioma; immunotherapy; molecular biology; targeted therapy; treatment
    DOI:  https://doi.org/10.3389/fimmu.2024.1537013
  5. Neuro Oncol. 2025 Jan 30. pii: noaf013. [Epub ahead of print]
    Extracellular Vesicles Released by Glioblastoma Cancer Cells Drive Tumor Invasiveness via Connexin-43 Gap Junctions.
    Matteo Tamborini, Valentino Ribecco, Elisabetta Stanzani, Arianna Sironi, Monica Tambalo, Davide Franzone, Elena Florio, Edoardo Fraviga, Chiara Saulle, Maria C Gagliani, Marco Pizzocri, Milena Mattioli, Katia Cortese, Jean X Jiang, Giuseppe Martano, Letterio S Politi, Marco Riva, Federico Pessina, Davide Pozzi, Simona Lodato, Lorena Passoni, Michela Matteoli.
       BACKGROUND: Although invasiveness is one of the major determinants of the poor glioblastoma (GBM) outcome, the mechanisms of GBM invasion are only partially understood. Among the intrinsic and environmental processes promoting cell-to-cell interaction processes, eventually driving GBM invasion, we focused on the pro-invasive role played by Extracellular Vesicles (EVs), a heterogeneous group of cell-released membranous structures containing various bioactive cargoes, which can be transferred from donor to recipient cells.
    METHODS: EVs isolated from patient-derived GBM cell lines and surgical aspirates were assessed for their pro-migratory competence by spheroid migration assays, calcium imaging, and PYK-2/FAK phosphorylation. Brain invasiveness was investigated in human cortical organoids-based assembloids and in vivo orthotopic xenografts. EV molecular features were specified by multiplex bead-based flow cytometry.
    RESULTS: Results unveil a self-sustaining mechanism triggering migration through autocrine release and engagement of a specific population of EVs of large size (L-EVs), isolated from either patient-derived cell lines or surgical aspirates. L-EVs act through modulation of calcium transients via Connexin 43-Gap Junctions (Cx43-GJ) and phospho-activation of PYK2. Pre-incubation with blocking antibodies targeting Cx43 hemichannels demonstrated a dose-dependent inhibition of the L-EV-mediated GBM migration. By exploiting patients' surgical aspirates, we show that only L-EVs deriving from tumoral cells, and not those with immune origin, promote tumor migration, impacting more prominently the tumoral cells with mesenchymal subtype.
    CONCLUSIONS: We demonstrate that L-EVs released by GBM cells, but not by the immune cells of the tumor microenvironment, represent a relevant and unique autocrine pro-migratory input for the tumor.
    Keywords:  Assembloids; Calcium signaling; Connexin-43; Extracellular vesicles; Focal adhesion complex; Glioblastoma; Invasion; Migration; Stem Cells; Surgical aspirate
    DOI:  https://doi.org/10.1093/neuonc/noaf013
  6. Neurooncol Adv. 2025 Jan-Dec;7(1):7(1): vdae201
    Therapeutic manipulation and bypass of the blood-brain barrier: powerful tools in glioma treatment.
    Alexandra M Giantini-Larsen, Abhinav Pandey, Andrew L A Garton, Margherita Rampichini, Graham Winston, Jacob L Goldberg, Rajiv Magge, Philip E Stieg, Mark M Souweidane, Rohan Ramakrishna.
      The blood-brain barrier (BBB) remains an obstacle for delivery of chemotherapeutic agents to gliomas. High grade and recurrent gliomas continue to portend a poor prognosis. Multiple methods of bypassing or manipulating the BBB have been explored, including hyperosmolar therapy, convection-enhanced delivery (CED), laser-guided interstitial thermal therapy (LITT), and Magnetic Resonance Guided Focused Ultrasound (MRgFUS) to enhance delivery of chemotherapeutic agents to glial neoplasms. Here, we review these techniques, currently ongoing clinical trials to disrupt or bypass the BBB in gliomas, and the results of completed trials.
    Keywords:  blood–brain barrier; convection-enhanced delivery; focused ultrasound; glioma; hyperosmolar therapy; laser interstitial thermal therapy
    DOI:  https://doi.org/10.1093/noajnl/vdae201
  7. Nat Commun. 2025 Jan 30. 16(1): 1095
    Oncolytic reprogramming of tumor microenvironment shapes CD4 T-cell memory via the IL6ra-Bcl6 axis for targeted control of glioblastoma.
    Jeffrey M Grimes, Sadashib Ghosh, Shamza Manzoor, Li X Li, Monica M Moran, Jennifer C Clements, Sherrie D Alexander, James M Markert, Jianmei W Leavenworth.
      Oncolytic viruses (OVs) emerge as a promising cancer immunotherapy. However, the temporal impact on tumor cells and the tumor microenvironment, and the nature of anti-tumor immunity post-therapy remain largely unclear. Here we report that CD4+ T cells are required for durable tumor control in syngeneic murine models of glioblastoma multiforme after treatment with an oncolytic herpes simplex virus (oHSV) engineered to express IL-12. The upregulated MHCII on residual tumor cells facilitates programmed polyfunctional CD4+ T cells for tumor control and for recall responses. Mechanistically, the proper ratio of Bcl-6 to T-bet in CD4+ T cells navigates their enhanced anti-tumor capacity, and a reciprocal IL6ra-Bcl-6 regulatory axis in a memory CD4+ T-cell subset, which requires MHCII signals from reprogrammed tumor cells, tumor-infiltrating and resident myeloid cells, is necessary for the prolonged response. These findings uncover an OV-induced tumor/myeloid-CD4+ T-cell partnership, leading to long-term anti-tumor immune memory, and improved OV therapeutic efficacy.
    DOI:  https://doi.org/10.1038/s41467-024-55455-9
  8. Clin Cancer Res. 2025 Jan 31.
    Corticosteroid-dependent association between prognostic peripheral blood cell-free DNA levels and neutrophil-mediated NETosis in patients with glioblastoma.
    Jacob E Till, Nicholas J Seewald, Zachariya Yazdani, Zhuoyang Wang, Dominique Ballinger, Heather Samberg, Siri Dandu, Camilla Macia, Melinda Yin, Aseel Abdalla, Timothy Prior, Shivani Shah, Thara Patel, Emily McCoy, Maikel Mansour, Carson A Wills, Veronica Bochenek, Jonathan Serrano, Matija Snuderl, Richard E Phillips, Donald M O'Rourke, Nduka M Amankulor, Ali Nabavizadeh, Arati S Desai, Kandace Gollomp, Zev A Binder, Wanding Zhou, Stephen J Bagley, Erica L Carpenter.
       PURPOSE: Non-invasive prognostic biomarkers to inform clinical decision-making are an urgent unmet need for the management of patients with glioblastoma (GBM). We previously showed that higher circulating cell-free DNA concentration [ccfDNA] is associated with worse survival in GBM. However, the biology underlying this is unknown.
    EXPERIMENTAL DESIGN: We prospectively enrolled 129 patients with treatment-naïve GBM with blood drawn prior to initial resection (baseline) and at time of first post-radiotherapy MRI. We performed ccfDNA methylation deconvolution to determine cellular sources of ccfDNA. ELISA was performed to detect citrullinated H3 (citH3), a marker of neutrophil extracellular traps (NETs). Multiplex proteomic analysis was used to measure soluble inflammatory proteins.
    RESULTS: We found that neutrophils contributed the highest proportion of prognostic ccfDNA. The percentage of ccfDNA derived from neutrophils was correlated with total [ccfDNA], but only in patients receiving pre-operative corticosteroids. At baseline and on-therapy, [citH3] was significantly higher in the plasma of patients with GBM receiving corticosteroids compared to corticosteroid-naïve GBMs or no-cancer controls. Unsupervised hierarchical clustering of ccfDNA methylation patterns yielded two clusters, with one enriched for patients with the NETosis phenotype and who received corticosteroids. Unsupervised clustering of circulating inflammatory proteins yielded similar results.
    CONCLUSIONS: These data suggest neutrophil-mediated NETosis is the dominant source of prognostic ccfDNA in patients with GBM and may be associated with glucocorticoid exposure. If further studies show that pharmacological inhibition of NETosis can mitigate the deleterious effects of corticosteroids, these plasma markers will have important clinical utility as non-invasive correlative biomarkers.
    DOI:  https://doi.org/10.1158/1078-0432.CCR-24-3169
  9. Clin Transl Med. 2025 Feb;15(2): e70187
    Spatial distribution of immune cells and their proximity to STING+ cells are associated with survival in glioblastoma.
    Hanwool Jeon, Hayeong Kang, Jihyun Im, Suin Jo, Hyunchul Jung, Moinay Kim, Jae Hyun Kim, Eunyeup Lee, Soyoung Kim, Jeong Hoon Kim, Chang-Ki Hong, Young-Hoon Kim, Sang Woo Song, Jinha Park, Sang-Yeob Kim, Seungjoo Lee.
      
    Keywords:  glioblastoma; multiplex IHC; spatial analysis; tumour immune microenvironment
    DOI:  https://doi.org/10.1002/ctm2.70187
  10. Neuro Oncol. 2025 Jan 27. pii: noaf024. [Epub ahead of print]
    Intestinal Bacteroides drives glioma progression by regulating CD8+ T cell tumor infiltration.
    Jit Chatterjee, Xuanhe Qi, Rui Mu, Xuanwei Li, Talia Eligator, Megan Ouyang, Stephanie L Bozeman, Rachel Rodgers, Somya Aggarwal, Danielle E Campbell, Lawrence A Schriefer, Megan T Baldridge, David H Gutmann.
       BACKGROUND: The intestinal microbiota regulates normal brain physiology and the pathogenesis of several neurological disorders. While prior studies suggested that this regulation operates through immune cells, the underlying mechanisms remain unclear. Leveraging two well characterized murine models of low-grade glioma (LGG) occurring in the setting of the neurofibromatosis type 1 (NF1) cancer predisposition syndrome, we sought to determine the impact of the gut microbiome on optic glioma progression.
    METHODS: Nf1-mutant mice genetically engineered to develop optic pathway gliomas (Nf1OPG mice) by 3 months of age were reared under germ-free (GF) conditions, treated with specific cocktails of antibiotics, or given fecal matter transplants (FMTs). Intestinal microbial species were identified by 16S genotyping. Neutralizing TGFβ antibodies were delivered systemically, while in vitro experiments used isolated murine microglia and T cells. Single cell RNA sequencing analysis was performed using established methods.
    RESULTS: Nf1 OPG mice raised in a GF environment or postnatally treated with vancomycin did not harbor optic gliomas or exhibit OPG-induced retinal nerve fiber layer thinning, which was reversed following conventionally raised mouse FMT or colonization with Bacteroides species. Moreover, this intestinal microbiota-regulated gliomagenesis was mediated by circulating TGFβ, such that systemic TGFβ neutralization reduced Nf1-OPG growth. TGFβ was shown to act on tumor-associated monocytes to induce Ccl3 expression and recruit CD8+ T cells necessary for glioma growth.
    CONCLUSIONS: Taken together, these findings establish, for the first time, a mechanistic relationship between Bacteroides in the intestinal microbiome and NF1-LGG pathobiology, suggesting both future predictive risk assessment strategies and therapeutic opportunities.
    Keywords:  Bacteroides; T cells; gut microbiota; low-grade glioma; tumor-associated monocytes
    DOI:  https://doi.org/10.1093/neuonc/noaf024
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