bims-malgli Biomed News
on Biology of malignant gliomas
Issue of 2025–12–14
eight papers selected by
Oltea Sampetrean, Keio University
  1. Multi-omic landscape of human gliomas from diagnosis to treatment and recurrence.
  2. Single cell spatial profiling of the matrisome identifies region-specific adhesion and signaling networks in glioblastoma.
  3. Recombination between fragile regions associated with chromosomal rearrangements in glioblastoma can be mediated by RAGs.
  4. Inhibiting the formation of neutrophil extracellular traps to prevent the recurrence of post-operative glioblastoma.
  5. INSM1 governs a neuronal progenitor state that drives glioblastoma in a human stem cell model.
  6. Enhanced lipid metabolism serves as a metabolic vulnerability to polyunsaturated fatty acids in glioblastoma.
  7. Gabapentin repurposing for glioblastoma therapy: Real-world data analyses augmented by use of active comparators.
  8. mRNA vaccine developed for sequential selective organ-to-cell targeting of glioma.
  1. Cancer Cell. 2025 Dec 11. pii: S1535-6108(25)00499-4. [Epub ahead of print]
    Multi-omic landscape of human gliomas from diagnosis to treatment and recurrence.
    Hadeesha Piyadasa, Benjamin Oberlton, Mikaela Ribi, Ke Leow, Jolene S Ranek, Inna Averbukh, Meelad Amouzgar, Candace C Liu, Davide G Franchina, Noah F Greenwald, Erin F McCaffrey, Rashmi Kumar, Selena Ferrian, Albert G Tsai, Ferda Filiz, Christine Camacho Fullaway, Marc Bosse, Sricharan Reddy Varra, Alex Kong, Cameron Sowers, Melanie Hayden Gephart, Pablo Nuñez-Perez, EnJun Yang, Mike Travers, Michael J Schachter, Samantha Liang, Maria R Santi, Samantha Bucktrout, Pier Federico Gherardini, John Connolly, Kristina Cole, Michael E Barish, Christine E Brown, Derek A Oldridge, Richard R Drake, Joanna J Phillips, Hideho Okada, Robert Prins, Sean C Bendall, Michael Angelo.
      Gliomas are among the most lethal cancers, with limited treatment options. To uncover hallmarks of therapeutic escape and tumor microenvironment (TME) landscape, we applied spatial proteomics, transcriptomics, and glycomics to 670 lesions from 310 adult and pediatric patients. Single-cell analysis shows high B7H3+ tumor cell prevalence in glioblastoma (GBM) and pleomorphic xanthoastrocytoma, while most gliomas, including pediatric cases, express targetable tumor antigens in less than 50% of tumor cells, potentially explaining trial failures. Paired samples of isocitrate dehydrogenase (IDH)-mutant gliomas reveal recurrence driven by tumor-immune spatial reorganization, shifting from T cell and vasculature-associated myeloid cell-enriched niches to microglia and CD206+ macrophage-dominated tumors. Multi-omic integration identified N-glycosylation as the best classifier of grade, while the immune transcriptome best predicted GBM survival. Provided as a community resource, this study offers a framework for glioma targeting, classification, outcome prediction, and a baseline of TME composition across all stages.
    Keywords:  GBM; TME; diffuse midline glioma; glioma; immune regulation; immunotherapy; single-cell profiling; spatial N-glycome; spatial multi-omics; tumor antigens
    DOI:  https://doi.org/10.1016/j.ccell.2025.11.006
  2. Commun Biol. 2025 Dec 09.
    Single cell spatial profiling of the matrisome identifies region-specific adhesion and signaling networks in glioblastoma.
    Arpan De, Santiago A Forero, Ali Pirani, John E Morales, Marisol De La Fuente-Granada, Sumod Sebastian, Jason T Huse, Leomar Y Ballester, Jeffrey S Weinberg, Frederick F Lang, Kadir C Akdemir, Joseph H McCarty.
      The human brain contains a milieu of extracellular matrix (ECM) components that promote normal development and physiology. ECM signaling pathways are often dysregulated in brain pathologies including the malignant cancer glioblastoma (GBM). Here, we used single-cell spatial transcriptomic platforms to map the expression of nearly 400 ECM genes in matching non-cancerous brain and GBM samples. At least four different GBM cell populations have been identified that show unique ECM expression profiles and spatial enrichment in distinct intratumor regions. Spatial mapping demonstrates largely non-overlapping expression signatures of ECM components in GBM stromal cell types, particularly in vascular endothelial cells and microglia/macrophages. Comparisons of GBM versus lower grade astrocytoma samples identifies differential expression of key ECM components. Computational analysis reveals novel ECM ligand-receptor networks between GBM and stromal cells. This spatial atlas provides new insights into ECM control of brain tumor initiation and progression and identifies potential targets for therapy in GBM.
    DOI:  https://doi.org/10.1038/s42003-025-09270-7
  3. iScience. 2025 Nov 21. 28(11): 113815
    Recombination between fragile regions associated with chromosomal rearrangements in glioblastoma can be mediated by RAGs.
    Amita Paranjape, Susmita Kumari, Lipsa Rani Sahu, Amrita Mondal, Swapna Kunhiraman, Arun Sharma M, Namrata M Nilavar, Bibha Choudhary, Sathees C Raghavan.
      The RAGs, comprising RAG1 and RAG2, catalyze V(D)J recombination by recognizing recombination-signal sequences (RSS). Glioblastoma, the aggressive brain cancer, has many oncogenic chromosomal alterations; however, the mechanism of their generation is largely unknown. Here, we report that RAGs are expressed in human glioblastoma cells at transcript and protein levels. RNA-seq data analysis confirmed the expression of RAGs in the majority of patients with glioma. Analysis of patient breakpoint sequences reveals cryptic RSS in regions undergoing rearrangements. Biochemical studies demonstrate that RAGs can bind and cleave cryptic RSS in fragile regions (AMY1B, CAMK2D, RN7SKP123-MTF2, DIPK1A, IRX5-IRX6), albeit at lower efficiency. Recombination assay using episomes harboring the fragile regions showed aberrant recombination in these regions, and the efficiency was significantly reduced in RAG1 ablated cells. Finally, we recapitulate the glioblastoma associated AMY1B and RN7SKP123-MTF2 chromosomal rearrangement using an extrachromosomal assay. Thus, the present study provides mechanistic insights into the generation of chromosomal aberrations associated with glioblastoma.
    Keywords:  cancer; chromosome organization; molecular interaction; transcriptomics
    DOI:  https://doi.org/10.1016/j.isci.2025.113815
  4. Nat Commun. 2025 Dec 09. 16(1): 10971
    Inhibiting the formation of neutrophil extracellular traps to prevent the recurrence of post-operative glioblastoma.
    Yaobao Han, Mengxiao Han, Tingting Wang, Hao Zhang, Hanghang Liu, Yanhui Zheng, Jun Dong, Zhen Li.
      Glioblastoma (GBM) is a highly malignant tumor with a high postoperative recurrence rate. It is crucial to develop innovative and effective approaches to prevent its recurrence. Herein, we focus on the important roles of neutrophil extracellular traps (NETs) in the progression of GBM in mice and patients. Neutrophils accumulate around the surgical cavity and release NETs to promote the proliferation and migration of postoperative residual GBM cells. Injection of a hydrogel loaded with copper selenide nanozyme and doxorubicin into the surgical cavity successfully inhibit the formation of NETs and improve the therapeutic efficacy against GBM. 60% of treated GBM mice survive over 24 months, which are 36 times longer than those of untreated mice, and close to the lifespan of healthy mice. The treated mice preserve their essential cognitive functions and basic motor ability. This study demonstrates the great potential of modulating NETs in GBM therapy.
    DOI:  https://doi.org/10.1038/s41467-025-65933-3
  5. Nat Commun. 2025 Dec 07.
    INSM1 governs a neuronal progenitor state that drives glioblastoma in a human stem cell model.
    Patrick A DeSouza, Matthew Ishahak, Xuan Qu, Colin McCornack, Devi Annamalai, Diane D Mao, Rajanikanth Vangipurapu, Yiwei Fu, Alexandre T Vessoni, Ryan T Cleary, Rowland H Han, Punn Augsornworawat, Timothy Woodiwiss, Darby Agovino, Braxton Sizemore, Jessica Kline, Maryam Borhani-Haghighi, Hao Chen, Sangami Pugazenthi, Hiroko Yano, Ting Wang, Luis F Z Batista, Jeffrey R Millman, Albert H Kim.
      Glioblastoma is a lethal brain cancer marked by functional plasticity driven by tumor cell-intrinsic mutations and their interplay with developmental programs. To investigate how canonical glioblastoma mutations promote functional plasticity, we have developed an isogenic human neural stem cell (NSC) model of glioblastoma by sequential addition of TERT promoter, TP53, and PDGFRA point mutations. TP53 loss-of-function increases TERT expression during serial mutagenesis, but only triple mutant NSCs reliably form lethal brain tumors in vivo that recapitulate glioblastoma. Tumor cell evolution triggers stress-related metabolic changes and transitions toward a neuronal progenitor network driven by transcription factor INSM1. INSM1 is highly expressed in human glioblastoma tumors and, during cortical development, in intermediate progenitor cells, which give rise to neurons. Remarkably, INSM1 knockdown in triple mutant NSCs and primary glioblastoma cells disrupts oncogenic gene expression and function and inhibits the in vivo tumorigenicity of triple mutant NSCs, highlighting the functional importance of an intermediate progenitor cell-like cell state in glioblastoma pathogenesis.
    DOI:  https://doi.org/10.1038/s41467-025-66371-x
  6. JCI Insight. 2025 Dec 09. pii: e191465. [Epub ahead of print]
    Enhanced lipid metabolism serves as a metabolic vulnerability to polyunsaturated fatty acids in glioblastoma.
    Shiva Kant, Yi Zhao, Pravin Kesarwani, Kumari Alka, Jacob F Oyeniyi, Ghulam Mohammad, Nadia Ashrafi, Stewart F Graham, C Ryan Miller, Prakash Chinnaiyan.
      Enhanced lipid metabolism, which involves the active import, storage, and utilization of fatty acids from the tumor microenvironment, plays a contributory role in malignant glioma transformation; thereby, serving as an important gain of function. In this work, through studies initially designed to understand and reconcile possible mechanisms underlying the anti-tumor activity of a high-fat ketogenic diet, we discovered that this phenotype of enhanced lipid metabolism observed in glioblastoma may also serve as a metabolic vulnerability to diet modification. Specifically, exogenous polyunsaturated fatty acids (PUFA) demonstrate the unique ability of short-circuiting lipid homeostasis in glioblastoma cells. This leads to lipolysis-mediated lipid droplet breakdown, an accumulation of intracellular free fatty acids, and lipid peroxidation-mediated cytotoxicity, which was potentiated when combined with radiation therapy. Leveraging this data, we formulated a PUFA-rich modified diet that does not require carbohydrate restriction, which would likely improve long-term adherence when compared to a ketogenic diet. The modified PUFA-rich diet demonstrated both anti-tumor activity and potent synergy when combined with radiation therapy in mouse glioblastoma models. Collectively, this work offers both a mechanistic understanding and a potentially translatable approach of targeting this metabolic phenotype in glioblastoma through diet modification and/or nutritional supplementation that may be readily integrated into clinical practice.
    Keywords:  Brain cancer; Metabolism; Metabolomics; Neuroscience; Oncology; Radiation therapy
    DOI:  https://doi.org/10.1172/jci.insight.191465
  7. Neuro Oncol. 2025 Dec 08. pii: noaf280. [Epub ahead of print]
    Gabapentin repurposing for glioblastoma therapy: Real-world data analyses augmented by use of active comparators.
    Christine Ann Pittman Ballard, Kevin M Goff, Mallika P Patel, Kyle M Walsh, Michelle Monje, Quinn T Ostrom.
      
    DOI:  https://doi.org/10.1093/neuonc/noaf280
  8. Nat Commun. 2025 Dec 11.
    mRNA vaccine developed for sequential selective organ-to-cell targeting of glioma.
    Lin Shi, Yueying Li, Shiyun Huang, Jin Peng, Chuyao Liu, Zuoyu Hu, Wenbin Deng, Guanjun Deng.
      Messenger RNA (mRNA)-based therapeutics hold great potential for effectively treating various diseases. However, the targeting of mRNA delivered by systemically administered lipid nanoparticles (LNP) is currently limited to the liver. Safe and efficient systemic delivery of mRNA to specific organs and cells remains a major challenge, and it is still unclear whether the positional isomerism of individual compounds within LNP affects their activity. Here, we synthesize a library of meta/ortho/para-ionizable lipidoids and prepare three-component lipid nanoparticles (tLNP) without PEG-lipids. Our findings show that tLNP containing meta-ionizable lipidoids (meta-tLNP) exhibits higher mRNA delivery efficiency than those containing ortho-/para-ionizable lipidoids (ortho-/para-tLNP). Additionally, we report a strategy termed Sequential Selective Organ-to-Cell Targeting (SSOCT), which enables the systemic administration of meta/ortho/para-tLNP to first achieve selective mRNA expression in the spleen, followed by targeted mRNA expression in dendritic cells within the spleen. Notably, we demonstrate that delivering the mRNA vaccine (mXO10 tLNP@mIDH1) using meta-tLNP effectively treats glioma in mice, particularly when combined with Anti-PD-1 therapy. This combination further enhances therapeutic efficacy, even completely eradicating glioma, reducing hepatotoxicity, and minimizing PEG-lipid-induced allergic reactions. This study establishes that mRNA therapy, developed by selectively targeting splenic dendritic cells via SSOCT, represents a promising therapeutic intervention for glioma.
    DOI:  https://doi.org/10.1038/s41467-025-67331-1
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