bims-malgli Biomed News
on Biology of malignant gliomas
Issue of 2025–12–21
eleven papers selected by
Oltea Sampetrean, Keio University
  1. Dynamic release of extracellular particles after opening of the blood-brain barrier predicts glioblastoma susceptibility to paclitaxel.
  2. Prognostic Significance of MGMT Promoter Methylation Status in IDH-mutant Glioma.
  3. Neural excitability promotes glioma growth.
  4. Local therapeutic platform prevents postsurgical GBM recurrence by diminishing GICs and reshaping immunosuppressive microenvironment.
  5. Diffuse midline gliomas get first FDA-approved drug.
  6. A human iPSC-based neural spheroid platform for modelling glioblastoma infiltration using high-content imaging.
  7. Oncogenic Ppm1d mutations deregulate the p53 pathway in primary mouse gliomas.
  8. Targeting chaperone-mediated autophagy inhibits properties of glioblastoma stem cells and restores anti-tumor immunity.
  9. Single cell proteomic analysis defines discrete neutrophil functional states in human glioblastoma.
  10. "Vorasidenib and Low-Grade Glioma: INDIGO Incremental Insights".
  11. Oncolytic HSV-1-Mediated JAG1 Blockade Induces Glioma Senescence-Associated Secretory Phenotype to Increase Macrophage Activation and Cetuximab-Mediated Senolysis.
  1. Nat Commun. 2025 Dec 16. 16(1): 11045
    Dynamic release of extracellular particles after opening of the blood-brain barrier predicts glioblastoma susceptibility to paclitaxel.
    Mark W Youngblood, Abha Kumari, Yoon-Tae Kang, Andrew Gould, Karl Habashy, Mateo Gomez, Harika Lingamarla, Trevor Morey, Li Chen, Harrshavasan Congivaram, Rachel Ward, Hui Zhang, Thomas K Sears, Kathleen McCortney, Katarzyna C Pituch, Elena M Torres Ponce, Ashkan Zarrieneh, Mariana Nieves, Sarah Vandermolen, Ditte Primdahl, Karan Dixit, Rimas V Lukas, Priya Kumthekar, Crismita Dmello, Guillaume Bouchoux, Michael Canney, Christina Amidei, Roger Stupp, Sunitha Nagrath, Adam M Sonabend.
      Liquid biopsies hold promise to improve the diagnosis, assessment of response to therapy, and ultimately guide the management of cancer patients. However, implementation of this approach in brain tumors has proven challenging due to the limited passage of molecules across the blood-brain barrier (BBB). We recently reported results from a phase I clinical trial in which the BBB was transiently opened in glioblastoma (GBM) patients using skull-implantable low-intensity pulsed ultrasound combined with microbubbles (LIPU/MB). In this study, treatment and BBB opening was performed every 3 weeks with paclitaxel administration until disease progression or up to 6 cycles (NCT04528680). As an exploratory objective of this trial, here we investigate extracellular vesicles and particles (EVPs/EPs) released into circulation in the context of tumor cell death as a potential biomarker for response to treatment. We develop and validate a microfluidic device designed to capture tumor-derived EVPs in glioblastoma patients (GlioExoChip). This approach leverages GBM-based expression of phosphatidylserine and Annexin-V chemistry that is traditionally used to measure apoptosis. EVPs are characterized using nanoparticle tracking analysis, proteomics, western blot, and scanning electron microscopy. Proteomic analysis of circulating EVPs isolated from GBM patients reveals distinct expression patterns to that of healthy individuals, and scRNA-seq analysis of these genes supported their tumoral origin within the GBM microenvironment. In vitro, paclitaxel-susceptible glioma cells treated with this drug exhibit apoptosis and dose-dependent EVP release. In concordance, we find changes in EVP release following the initiation of paclitaxel with LIPU/MB correlated with overall survival in GBM patients. Thus, our study introduces an efficient microfluidic platform for the capture of circulating GBM EVPs and demonstrates that release upon BBB opening is predictive of outcomes following paclitaxel treatment. This approach represents a real-time surrogate biomarker for treatment response for a disease where imaging-based assessment of response has not been shown to be reliable. Future prospective validation is warranted.
    DOI:  https://doi.org/10.1038/s41467-025-65681-4
  2. Neuro Oncol. 2025 Dec 15. pii: noaf287. [Epub ahead of print]
    Prognostic Significance of MGMT Promoter Methylation Status in IDH-mutant Glioma.
    Gilbert Youssef, Elisa Aquilanti, Julie J Miller, Zhou Lan, Aleksandra B Lasica, Isabel Arrillaga-Romany, Tracy T Batchelor, Tamar R Berger, Rameen Beroukhim, Ugonma Chukwueke, Jorg Dietrich, Deborah A Forst, Elizabeth R Gerstner, L Nicolas Gonzalez Castro, Justin T Jordan, J Ricardo Mcfaline-Figueroa, Eudocia Quant Lee, Lakshmi Nayak, Vihang Nakhate, Juan Pablo Ospina, Scott R Plotkin, Nancy Wang, John Y Rhee, David A Reardon, Patrick Y Wen.
       BACKGROUND: The prognostic and predictive value of O6-methylguanine-DNA methyltransferase promoter (MGMTp) methylation is not well established in isocitrate dehydrogenase (IDH)-mutant gliomas. This study evaluates the survival impact of MGMTp and other clinical, molecular, and radiologic variables in low-grade and high-grade IDH-mutant gliomas.
    METHODS: We retrospectively evaluated 520 consecutive adult patients treated for an initial diagnosis of IDH-mutant glioma, of any histological grade, at two large academic institutions. MGMTp methylation was evaluated by methylation-specific polymerase chain reaction (PCR) analysis. Log-rank test and Cox proportional hazards model were applied to evaluate the association of clinical, molecular, and radiological characteristics with overall survival (OS) and progression-free survival (PFS).
    RESULTS: Median age was 36.6 years; MGMTp was methylated in 70% and unmethylated in 30%. MGMTp methylation was not significantly associated with PFS (p = 0.74) but trended towards significance for OS (p = 0.11) on multivariate analyses. Cyclin dependent kinase inhibitor 2A/B (CDKN2A/B) homozygous deletion [HR = 3.26 (1.47, 7.23, p = 0.006] and an integrated grade 4 classification [HR = 2.08 (1.06, 4.67), p = 0.048] were strong predictors of OS in astrocytoma, whereas maximal resection [HR = 0.06 (0.01, 0.57), p = 0.016] and radiation [HR = 0.41 (0.18, 0.91), p = 0.03] were strong prognosticators for PFS in the entire cohort. Maximal resection of the enhancing disease [HR = 0.17 (0.05, 0.96), p = 0.014] and radiation [HR = 0.47 (0.19, 0.65), p = 0.046] were strongly associated with PFS in grade 2 and 3 gliomas.
    CONCLUSION: MGMTp methylation was not associated with a prognostic or predictive value in our IDH-mutant glioma cohort. CDKN2A/B status and extent of resection were strong predictors of outcomes.
    Keywords:  IDH-mutant glioma; MGMT promoter methylation; prognosis
    DOI:  https://doi.org/10.1093/neuonc/noaf287
  3. Nat Rev Neurosci. 2025 Dec 16.
    Neural excitability promotes glioma growth.
    Katherine Whalley.
      
    DOI:  https://doi.org/10.1038/s41583-025-01017-x
  4. Nat Commun. 2025 Dec 18.
    Local therapeutic platform prevents postsurgical GBM recurrence by diminishing GICs and reshaping immunosuppressive microenvironment.
    Mengxi Zhu, Mengting Yang, Rui Li, Xiwen Hu, Jiaxuan Chen, Limin Xu, Sunhui Chen, Tao Li, Jianxin Wang, Bin Zheng, Huining He.
      Glioblastoma multiforme (GBM) is characterized by aggressive invasiveness and poor prognosis, and presents a significant clinical challenge due to incomplete surgical resection, poor blood‒brain barrier penetration of therapeutic agents, and inevitable recurrence mainly driven by residual glioma-initiating cells (GICs) and an immunosuppressive microenvironment. Therefore, there is an urgent need to kill remaining GICs and reverse the immunosuppressive tumor microenvironment to prevent postoperative recurrence of GBM. Here, we design an injectable therapeutic platform that targets and kills remaining GICs and reverses the immunosuppressive microenvironment after postoperative resection to prevent the recurrence of GBM. This platform comprises GIC-targeting exosomes that carry siRNA for Notch1 and mitoxantrone to reduce the stemness of GICs and kill residual GICs and glioma cells, respectively, and an immune activator (interleukin-12), which can remodel the immunosuppressive tumor microenvironment, ultimately suppressing postoperative GBM relapse. Our work provides a perspective into the effective inhibition of postresection recurrence of GBM.
    DOI:  https://doi.org/10.1038/s41467-025-67415-y
  5. Cancer. 2025 Dec 15. 131(24): e70146
    Diffuse midline gliomas get first FDA-approved drug.
    Leah Lawrence.
      
    DOI:  https://doi.org/10.1002/cncr.70146
  6. Sci Rep. 2025 Dec 13.
    A human iPSC-based neural spheroid platform for modelling glioblastoma infiltration using high-content imaging.
    Victoria S K Tsang, Federica Riccio, Aimee S Wilson, Hannah Nudds, Jason D Coombes, Heiko Wurdak, Harry J C J Bulstrode, Ivo Lieberam, Davide Danovi.
      Glioblastoma is the most aggressive adult brain tumour, characterised by resistance to therapy and high recurrence due to diffuse infiltration. We developed a physiologically relevant co-culture model, combining patient-derived glioblastoma cell lines with cortical-like neural spheroids differentiated from human induced pluripotent stem cells. Using high-content imaging, we demonstrate that GBM20 and GBM1 cell lines migrate directionally along axons toward neural spheroids in live imaging assays and infiltrate spheroids extensively in endpoint assays, unlike non-cancerous neural stem cells. A proof-of-principle drug screen identified PF 573228 (FAK inhibitor) and motixafortide (CXCR4 inhibitor) as potent suppressors of GBM20 and GBM1 infiltration, respectively. Bulk RNA sequencing revealed gene expression profiles correlating with invasive behaviour and drug sensitivity. This platform offers a valuable model for studying glioblastoma infiltration along axons and provides proof-of-principle that migration can serve as a measurable and actionable phenotype to screen therapeutic vulnerabilities in glioblastoma.
    Keywords:  Cancer migration; Glioblastoma; High-content imaging; Induced-pluripotent stem cells; Neural spheroid; Stem cell modelling
    DOI:  https://doi.org/10.1038/s41598-025-30914-5
  7. bioRxiv. 2025 Nov 28. pii: 2025.11.25.690483. [Epub ahead of print]
    Oncogenic Ppm1d mutations deregulate the p53 pathway in primary mouse gliomas.
    Vennesa Valentine, Abigail J Groth, Joshua Tolliver, Avneesh Saravanapavan, Spencer M Maingi, Loren B Weidenhammer, Nerissa T Williams, Lixia Luo, Matthew S Waitkus, Sheeba Jacob, Zachary J Reitman.
       Importance of Study: Protein phosphatase magnesium-dependent 1D (PPM1D) is frequently mutated in diffuse midline gliomas (DMGs). DMGs are rare pediatric brain tumors with limited treatment options. Due to the cancer's rapid progression, patients usually survive 12-24 months after diagnosis. This underscores the critical need to better understand the molecular mechanisms driving DMGs. This study describes a novel mouse model that provides a powerful platform to investigate PPM1D-driven tumor biology and offers mechanistic insights into disease development and progression. Furthermore, it serves as a valuable preclinical system for evaluating therapeutic strategies and identifying translational opportunities to target Ppm1d-mutant tumors.
    Background: Diffuse midline gliomas (DMGs) are incurable brain tumors with limited treatment options. Approximately 20% of DMGs harbor truncating mutations in exon 6 of phosphatase PPM1D , which stabilize the protein and deregulate p53 signaling. However, the consequences of these mutations for tumor initiation, progression, and therapy remain unclear.
    Methods: We developed a conditional Ppm1d-loxP-exon6-loxP-exon6-E518X-tag mouse allele ( Ppm1d-flex-6 ) that enables lineage-, spatial-, and temporal-specific expression of a DMG-derived truncated Ppm1d protein from its endogenous locus in the presence of Cre-recombinase. Ubiquitous activation of mutant Ppm1d was modeled using the Meox2-Cre driver, and primary gliomas were modeled using the RCAS/tv-a system to introduce Cre and PDGFB co-drivers into Nestin-positive neural stem cells. Complementary studies were performed in mouse embryonic fibroblasts (MEFs) expressing truncated Ppm1d following Cre recombination.
    Results: While Meox2-Cre-driven ubiquitous recombination of Ppm1d-flex-6 produced muted phenotypes, Ppm1d-flex-6 recombination in Nestin+ neural stem cells accelerated gliomagenesis. Its oncogenic effect was weaker than complete p53 loss, and it did not accelerate tumorigenesis further in p53-null tumors. Single-cell RNA-sequencing revealed that Ppm1d-flex-6 gliomas adopt more progenitor-like transcriptional states and upregulate p53- and cell cycle associated pathways. In MEFs, Ppm1d-flex-6 enhanced proliferation and shifted transcriptomic programs toward MAPK and PI3K-Akt signaling, while impairing DNA damage responses, including reduced γ-H2AX induction after irradiation. These defects sensitized cells to radiation and decreased clonogenic survival after ionizing radiation and PARP inhibition.
    Conclusions: Ppm1d mutations confer intermediate suppression of the p53 pathway, consistent with the clinical features of PPM1D -mutant DMGs and are associated with radiosensitivity and PARP inhibitor vulnerability.
    DOI:  https://doi.org/10.1101/2025.11.25.690483
  8. Nat Commun. 2025 Dec 13.
    Targeting chaperone-mediated autophagy inhibits properties of glioblastoma stem cells and restores anti-tumor immunity.
    Yonghua Li, Min Sheng, Weijie Li, Simin Liu, Botao Wang, Bing Liu, Mei Luo, Xiao Zhou, Qiaoxi Xia, Shihong Hong, Ziyuan Zheng, Shi-Yuan Cheng, Xiaobing Jiang, Junjun Li, Tianzhi Huang.
      Chaperone-mediated autophagy (CMA) is a selective autophagic process essential for maintaining cellular quality and responding to stress. Dysregulation of the CMA pathway is increasingly recognized in various cancers, yet the mechanisms behind CMA hyperactivation in cancer cells remain unclear. Here, we show that CMA is upregulated in patient-derived glioblastoma stem cells (GSCs), indicated by a significant increase in the lysosomal abundance of the CMA receptor, lysosome-associated membrane protein 2 A (LAMP2A). This increase results from MST4-mediated phosphorylation of LAMP2A, enhancing its stability and promoting homotrimer formation while inhibiting degradation by Cathepsin A. CMA supports GSC proliferation and self-renewal by activating mTORC1 through the selective degradation of its negative regulators, TSC1 and TSC2. Additionally, CMA is involved in epigenetic silencing of the cGAS-STING pathway, promoting tumor immune escape via lysosomal degradation of the DNA demethylase TET3. Inhibition of CMA synergizes with immune checkpoint therapy in glioblastoma models, highlighting a potential therapeutic target.
    DOI:  https://doi.org/10.1038/s41467-025-67119-3
  9. Nat Commun. 2025 Dec 15.
    Single cell proteomic analysis defines discrete neutrophil functional states in human glioblastoma.
    Pranvera Sadiku, Alejandro J Brenes, Rupert L Mayer, Leila Reyes, Patricia Coelho, Gabi van Stralen, Ailiang Zhang, Manuel A Sanchez-Garcia, Emily R Watts, Imran Liaquat, Andrew J M Howden, Ikeoluwa Adekoya, Anuka Boldbaatar, Allan MacRaild, Sarah Risbridger, Gillian M Morrison, Heather MacPherson, Caroline M Bruce, Shonna Johnston, Robert Grecian, Fiona A Murphy, Steven M Pollard, Paul M Brennan, Karl Mechtler, Sarah R Walmsley.
      Neutrophils are vital innate immune cells shown to infiltrate glioblastomas, however we currently lack the molecular understanding of their functional states within the tumour niche. Given that neutrophils are known to display a prominent discordance between mRNA and protein abundance, we developed ultra-sensitive mini-bulk and single cell proteomic (SCP) workflows to study the heterogeneity of peripheral blood and tumour associated neutrophils (TAN) from patients with glioblastoma. Mini-bulk analysis enabled a deeper protein coverage of circulating immature, mature and TAN populations, defining signatures of maturity and demonstrating that TANs resemble mature circulating neutrophils. Analysis of the SCP data results in the detection of >1100 proteins from a single TAN providing a detailed characterization of neutrophil subsets in glioblastoma. Our approach shows evidence of pathogenic and anti-tumorigenic clusters and discovers cell states invisible to scRNAseq, opening new opportunities to selectively target pro-tumoural neutrophil states.
    DOI:  https://doi.org/10.1038/s41467-025-67367-3
  10. Neuro Oncol. 2025 Dec 14. pii: noaf284. [Epub ahead of print]
    "Vorasidenib and Low-Grade Glioma: INDIGO Incremental Insights".
    David Schiff.
      
    DOI:  https://doi.org/10.1093/neuonc/noaf284
  11. Cancer Res. 2025 Dec 18.
    Oncolytic HSV-1-Mediated JAG1 Blockade Induces Glioma Senescence-Associated Secretory Phenotype to Increase Macrophage Activation and Cetuximab-Mediated Senolysis.
    Kimberly A Rivera-Caraballo, Tae Jin Lee, Arnoneel Sinha, Marco Orecchioni, Rafal Pacholczyk, Karina Vázquez-Arreguín, Shilpa Sharma, Kimya Jones, Kailash Vemuri, Upasana Sahu, Sara A Murphy, Bangxing Hong, Ravindra Kolhe, Ashok Sharma, Balveen Kaur.
      Oncolytic HSV-1 (oHSV) treatment induces Notch signaling and myelosuppression in the tumor microenvironment (TME) of preclinical cancer models. Clinically, the Notch ligand JAG1 was upregulated in recurrent high-grade glioma patients treated with the oHSV CAN-3110 and correlated with poor prognosis. To better understand endogenous JAG1-mediated signaling in glioma cells and tumor-associated macrophages (TAMs), we engineered a JAG1-antagonizing oHSV (OD-0J1) and interrogated its impact on cancer and myeloid cells in the tumor microenvironment. OD-0J1 antagonized JAG1-mediated Notch signaling and suppressed tumor growth in athymic nude and humanized mice, an effect reliant on Notch signaling in tumor cells. Kinome profiling revealed that OD-0J1 treatment suppressed CDK1, resulting in activation of the G2/M cell cycle checkpoint. Cell cycle arrest led to senescence and correlated with increased reactive oxygen species, p62 and autophagosome accumulation, and senescence-associated β-galactosidase activity. OD-0J1-induced senescence resulted in increased production of inflammatory chemokines and DAMPs, such as IL-1β, HMGB1, and extracellular ATP. Co-culturing macrophages with OD-0J1-infected tumor cells led to stimulation of chemotactic and pro-inflammatory pathways, as well as increased Fc receptor activation. Single-cell RNA sequencing and flow cytometric analysis of F4/80+ cells isolated from tumors showed a shift from tumor-supporting TAMs to inflammatory macrophages upon OD-0J1 treatment. Heightened EGFR activation in senescent cells was a mechanism to escape cell death, which created a unique opportunity for cetuximab as a senolytic agent. Combination therapy reduced EGFR signaling and induced macrophage-mediated antibody-dependent cellular cytotoxicity, thereby increasing the anti-tumor therapeutic efficacy of OD-0J1.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-25-1402
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