bims-malgli Biomed News
on Biology of malignant gliomas
Issue of 2025–09–07
eleven papers selected by
Oltea Sampetrean, Keio University
  1. The neuroscience of brain cancers.
  2. Targeting TGFβ docking receptor Glycoprotein A Repetitions Predominant (GARP) via novel chimeric antigen receptor (CAR)-T cell platform to treat glioblastoma.
  3. DNA damage response profile distinguishes poor-acting gliomas with shared methylome signatures.
  4. Glioblastoma Tumor Microtubes and Brain Fatty Acid-binding Protein: Path to Directional Infiltration.
  5. Rewiring of cortical glucose metabolism fuels human brain cancer growth.
  6. Response to anti-angiogenic therapy is associated with AIMP protein family expression in glioblastoma and lower-grade gliomas.
  7. Deregulating m6A regulators leads to altered RNA biology in glioma cell lines.
  8. Glioblastoma hijacks cholinergic networks.
  9. Molecularly matched targeted therapies plus radiotherapy in glioblastoma: the phase 1/2a N2M2 umbrella trial.
  10. Spatial profiling of longitudinal glioblastoma reveals consistent changes in cellular architecture, post-treatment.
  11. AI-driven WHO 2021 classification of gliomas based only on H&E-stained slides.
  1. Neuron. 2025 Sep 03. pii: S0896-6273(25)00519-7. [Epub ahead of print]113(17): 2734-2739
    The neuroscience of brain cancers.
    Michelle Monje.
      In the central nervous system (CNS), where neuronal activity promotes brain development and plasticity, including glial precursor cell proliferation, the activity of neurons robustly drives the initiation, growth, invasion, treatment resistance, and progression of brain cancers such as adult and pediatric hemispheric high-grade gliomas, diffuse midline gliomas such as diffuse intrinsic pontine glioma (DIPG), and pediatric low-grade optic gliomas. The underlying mechanisms involve both neuronal-activity-regulated paracrine signaling and direct electrochemical communication through neuron-to-glioma synapses. Neuronal inputs to tumors can then be propagated through connections between cancer cells. In turn, brain cancers such as gliomas remodel neural circuits to increase excitability, thereby augmenting the tumor-promoting effects of brain activity and contributing to tumor-associated seizures and neurological impairments, including cognitive deficits. These principles of neuron-cancer interactions are proving to be relevant to other cancers in the brain and the body, underscoring the importance of approaching cancers from a neuroscience perspective.
    Keywords:  DIPG/DMG; brain cancer; cancer neuroscience; glioblastoma; glioma
    DOI:  https://doi.org/10.1016/j.neuron.2025.07.012
  2. Neuro Oncol. 2025 Aug 27. pii: noaf195. [Epub ahead of print]
    Targeting TGFβ docking receptor Glycoprotein A Repetitions Predominant (GARP) via novel chimeric antigen receptor (CAR)-T cell platform to treat glioblastoma.
    Bill Xingjun Wu, Daniel Kreatsoulas, Hakan Cam, Chelsea Bolyard, Yuzhou Chang, Jay Mandula, Parker W Welsh, Ziyu Wang, Anqi Li, Payton Weltge, J Bradley Elder, Pierre Giglio, Jose J Otero, Prajwal Rajappa, Damien Gerald, Dongjun Chung, Qin Ma, Maria Velegraki, Zihai Li I.
       BACKGROUND: Glycoprotein A-repetitions predominant (GARP) is a cell surface non-signaling receptor for docking and activating latent transforming growth factor beta (LTGFβ) expressed by regulatory T cells, platelets and tumor cells. In lung and breast cancers, its expression correlates with advanced stage and poor prognosis - suggesting that GARP could act as a therapeutic target. This study examines the therapeutic impact of targeting GARP in glioblastoma (GBM) via a novel anti-GARP chimeric antigen receptor-expressing T cell (CAR-T) modality in murine models of GBM.
    METHODS: We examined multiple human glioma databases to correlate the expression of GARP with clinical outcomes. We then performed multi-plex imaging of human GBM samples to understand the impact of GARP expression on the tumor microenvironment (TME). Importantly, we developed a novel anti-GARP CAR-T cell strategy to treat GBM. We examine if this therapy is efficacious against orthotopic models of GBM, in both immunocompetent syngeneic and immunodeficient mice.
    RESULTS: We demonstrate that elevated GARP expression in human GBM correlates with poor overall survival, mesenchymal subtype, and gene signatures associated with angiogenesis and immune exclusion in the TME. Our novel anti-GARP CAR-T is efficacious in vitro and in vivo, against multiple preclinical models of GBM including patient-derived xenograft (PDX) models without significant toxicity.
    CONCLUSIONS: GARP-LTGFβ plays a key role in the development and prognostics of GBM and GARP-targeted CAR-T therapy shows promising efficacy and safety in murine orthotopic GBM models. A first-in-human phase I clinical trial for patients with recurrent GBM began to enroll patients in May 2025 (NCT06964737).
    Keywords:  CAR-T cells; GARP; TGFβ; cancer immunotherapy; glioblastoma
    DOI:  https://doi.org/10.1093/neuonc/noaf195
  3. Neuro Oncol. 2025 Aug 27. pii: noaf199. [Epub ahead of print]
    DNA damage response profile distinguishes poor-acting gliomas with shared methylome signatures.
    Nalin Leelatian, Charu Singh, Richard Bouffard, Ranjini K Sundaram, Kirsten E Diggins, William Sullivan, Sateja Paradkar, Zeynep Erson Omay, Bret C Mobley, Susan E Gueble, Juan C Vasquez, Ranjit S Bindra.
       BACKGROUND: Therapies for diffuse glioma induce DNA damage response (DDR), and strategies to exploit DDR defects are active areas of investigation. While global DNA methylation profiling effectively classifies gliomas into subtypes, the epigenetic and gene expression patterns of DDR genes, and their contribution to tumor classification and outcomes, have yet to be fully elucidated. Thus, dissecting the DDR epigenetics, gene expression, and single-cell heterogeneity may reveal key molecular characteristics, refine prognosis, and identify novel treatment strategies and resistance mechanisms.
    METHODS: We characterized DDR epigenetics and gene expression of TCGA glioblastomas (GBM) and low-grade gliomas (LGG). Single-cell protein analysis by imaging mass cytometry (IMC) was performed on a separate cohort of 118 diffuse gliomas.
    RESULTS: Analysis of TCGA cohorts revealed two DDR methylation groups that correlated with IDH mutation status and previously reported molecular groups. DDR transcription profiling further classified tumors into four groups. Those with high DDR transcription across pathways were linked to poor survival independent of IDH or MGMT status, and potentially improved prognostication beyond established biomarkers. Single-cell characterization of a separate cohort revealed intratumoral DDR diversity and identified proliferative tumor cells with high DDR protein expression across pathways that are associated with unfavorable grade and survival.
    CONCLUSIONS: Tumor-level epigenetic and transcriptional DDR signatures alone can distinguish molecular-defined diagnosis and outcomes of gliomas beyond established biomarkers. A higher abundance of glioma cells with high DDR effector expression across pathways is associated with poor survival. Thus, clinical assessment of pan-DDR expression may inform prognosis and identify potential therapeutic targets.
    Keywords:  DNA damage response; glioma; methylation; single cell; transcriptomics
    DOI:  https://doi.org/10.1093/neuonc/noaf199
  4. Neuro Oncol. 2025 Aug 28. pii: noaf200. [Epub ahead of print]
    Glioblastoma Tumor Microtubes and Brain Fatty Acid-binding Protein: Path to Directional Infiltration.
    Won-Shik Choi, Pureunsol Jeon, Seth Peyton, Mansi Garg, John Maringa Githaka, Rong-Zong Liu, Darryl D Glubrecht, Amirali B Bukhari, Daniel McGinn, Lubna Yasmin, Caitlin Mak, Xia Xu, Matthew P Larocque, Xuejun Sun, Frank K H van Landeghem, Karolyn Au, Ing Swie Goping, Roseline Godbout.
       BACKGROUND: Glioblastoma (GBM) is a deadly brain cancer with a dismal prognosis. There is evidence that infiltration and therapy resistance in GBM are driven by tumor microtubes (TMs), ultra-long membrane-enclosed protrusions that serve as intercellular communication channels. The aims of this study were to investigate the role of TMs and identify the molecular drivers involved in TM formation.
    METHODS: We used patient-derived GBM neurosphere cultures that produce TMs to investigate TM dynamics, the proteins and pathways involved in TM formation, and the effect of targeting brain fatty acid-binding protein (FABP7) on mouse survival using an orthotopic model of GBM.
    RESULTS: The radial glial cell marker, FABP7, is highly expressed in TMs. Like GAP43, FABP7 is critically important for the formation of TMs in GBM neurosphere cultures. We show that GBM cells use TMs as a fiber network for rapid and directional migration. Our results indicate that GAP43 phosphorylation is required for TM formation, with GAP43 phosphorylation facilitated by FABP7 expression. We also show that depletion or inhibition of protein kinase C (PKC), the kinase responsible for GAP43 phosphorylation, decreases TM formation. Targeting FABP7 in an orthotopic mouse model of TM-forming GBM cells increases survival but does not sensitize tumors to radiation.
    CONCLUSIONS: We found that the FABP7-PKC-pGAP43 axis is key to GBM TM formation, with TMs serving as networks for efficient long-distance cell migration. Our results indicate that TM formation can be mitigated by FABP7 inhibition with the potential of improving clinical outcomes in GBM patients.
    Keywords:  GAP43; fatty acid-binding protein 7; glioblastoma; protein kinase C; tumor microtubes
    DOI:  https://doi.org/10.1093/neuonc/noaf200
  5. Nature. 2025 Sep 03.
    Rewiring of cortical glucose metabolism fuels human brain cancer growth.
    Andrew J Scott, Anjali Mittal, Baharan Meghdadi, Alexandra O'Brien, Justine Bailleul, Palavalasa Sravya, Abhinav Achreja, Weihua Zhou, Jie Xu, Angelica Lin, Kari Wilder-Romans, Ningning Liang, Ayesha U Kothari, Navyateja Korimerla, Donna M Edwards, Zhe Wu, Jiane Feng, Sophia Su, Li Zhang, Peter Sajjakulnukit, Anthony C Andren, Junyoung O Park, Johanna Ten Hoeve, Vijay Tarnal, Kimberly A Redic, Nathan R Qi, Joshua L Fischer, Ethan Yang, Michael S Regan, Sylwia A Stopka, Gerard Baquer, Krithika Suresh, Jann N Sarkaria, Theodore S Lawrence, Sriram Venneti, Nathalie Y R Agar, Erina Vlashi, Costas A Lyssiotis, Wajd N Al-Holou, Deepak Nagrath, Daniel R Wahl.
      The brain avidly consumes glucose to fuel neurophysiology1. Cancers of the brain, such as glioblastoma, relinquish physiological integrity and gain the ability to proliferate and invade healthy tissue2. How brain cancers rewire glucose use to drive aggressive growth remains unclear. Here we infused 13C-labelled glucose into patients and mice with brain cancer, coupled with quantitative metabolic flux analysis, to map the fates of glucose-derived carbon in tumour versus cortex. Through direct and comprehensive measurements of carbon and nitrogen labelling in both cortex and glioma tissues, we identify profound metabolic transformations. In the human cortex, glucose carbons fuel essential physiological processes, including tricarboxylic acid cycle oxidation and neurotransmitter synthesis. Conversely, gliomas downregulate these processes and scavenge alternative carbon sources such as amino acids from the environment, repurposing glucose-derived carbons to generate molecules needed for proliferation and invasion. Targeting this metabolic rewiring in mice through dietary amino acid modulation selectively alters glioblastoma metabolism, slows tumour growth and augments the efficacy of standard-of-care treatments. These findings illuminate how aggressive brain tumours exploit glucose to suppress normal physiological activity in favour of malignant expansion and offer potential therapeutic strategies to enhance treatment outcomes.
    DOI:  https://doi.org/10.1038/s41586-025-09460-7
  6. Cancer Res Commun. 2025 Aug 28.
    Response to anti-angiogenic therapy is associated with AIMP protein family expression in glioblastoma and lower-grade gliomas.
    Humaira Noor, Yuanning Zheng, Haruka Itakura, Olivier Gevaert.
      Glioblastoma (GBM) is a highly vascularized, heterogeneous tumor, yet anti-angiogenic therapies have yielded limited survival benefits. The lack of validated predictive biomarkers for treatment response stratification remains a major challenge. Aminoacyl tRNA synthetase complex-interacting multicomplex proteins (AIMPs) 1/2/3 have been implicated in CNS diseases, but their roles in gliomas remain unexplored. We investigated their association with angiogenesis and their significance as predictive biomarkers for anti-angiogenic treatment response. In this multi-cohort retrospective study we analyzed glioma samples from TCGA, CGGA, Rembrandt, Gravendeel, BELOB and REGOMA trials, and four single-cell transcriptomic datasets. Multi-omic analyses incorporated transcriptomic, epigenetic, and proteomic data. Kaplan-Meier and Cox proportional hazards models were used to assess the potential prognostic value of AIMPs in heterogeneous and homogeneous treatment-groups. Using single-cell transcriptomics, we explored spatial and cell-type-specific AIMP2 expression in GBM. AIMP1/2/3 expressions correlated significantly with angiogenesis across TCGA cancers. In gliomas, AIMPs were upregulated in tumor vs. normal tissues, higher- vs. lower-grade gliomas, and recurrent vs. primary tumors (p<0.05). Upon retrospective analysis of two clinical trials assessing different anti-angiogenic drugs, we found that high-AIMP2 subgroups had improved response to therapies in GBM (REGOMA: HR 4.75 [1.96-11.5], p<0.001; BELOB: HR 2.3 [1.17-4.49], p=0.015). AIMP2-cg04317940 methylation emerged as a clinically applicable stratification marker. Single-cell analysis revealed homogeneous AIMP2 expression in tumor tissues, particularly in AC-like cells, suggesting a mechanistic link to tumor angiogenesis. These findings provide novel insights into the role of AIMPs in angiogenesis, offering improved patient stratification and therapeutic outcomes in recurrent GBM.
    DOI:  https://doi.org/10.1158/2767-9764.CRC-25-0170
  7. bioRxiv. 2025 Aug 19. pii: 2024.10.28.620763. [Epub ahead of print]
    Deregulating m6A regulators leads to altered RNA biology in glioma cell lines.
    Syeda Maheen Batool, Hanna Lee, Ana K Escobedo, Denalda Gashi, Kesli Faber, Prerna Khanna, Kase D Haas, Tiffaney Hsia, Bob S Carter, Leonora Balaj.
      N6-methyladenosine (m6A) is the most prevalent internal mRNA modification, enriched in the CNS yet poorly characterized in glioma. Using long-read RNA sequencing, we mapped m6A in an in vitro glioma model following knockdown (KD) of the reader IGF2BP2, writer METTL3, and eraser ALKBH5, with naive glioma cells and astrocytes as controls. Glioma cells exhibited a two-fold reduction in global m6A, suggesting progressive loss from healthy to malignant states. Integrated analysis revealed that m6A mediated control of gene expression is influenced by modification topology (CDS:3'UTR), transcript biotype, and length. Regulator KD, particularly ALKBH5 induced redistribution of m6A toward 3'UTR with consequent gene upregulation. We also identified m6A-mediated isoform switching, with a higher usage of retained intron and nonsense-mediated decay isoforms. Structural and splicing alterations at the isoform level were identified unique to each KD condition indicating m6A driven aberrant alternative splicing. At the functional level, KD specific remodeling of oncogenic signaling was also observed. ALKBH5 KD suppressed MYC targets and pro-apoptotic signaling while METTL3 KD enhanced mTOR and PI3K-AKT signaling. Collectively, these results demonstrate that m6A mediated regulation in glioma is highly context-dependent, defining distinct clinically relevant phenotypes. This has implications for future biomarker discovery and development of targeted therapeutics.
    Keywords:  N6-methyladenosine (m6A); RNA; alternative splicing; epitranscriptomics; glioma; isoform; signaling
    DOI:  https://doi.org/10.1101/2024.10.28.620763
  8. Cancer Cell. 2025 Aug 25. pii: S1535-6108(25)00360-5. [Epub ahead of print]
    Glioblastoma hijacks cholinergic networks.
    Yen Vu, Moran Amit.
      Glioblastoma alters normal brain function by hijacking neural circuits. In this issue of Cancer Cell, Yang et al. elucidate the mechanisms by which glioblastoma exploits cholinergic signaling pathways to disrupt the hierarchical organization of brain networks. These insights help redefine tumor-brain interactions and open new therapeutic avenues.
    DOI:  https://doi.org/10.1016/j.ccell.2025.08.003
  9. Nat Med. 2025 Sep 05.
    Molecularly matched targeted therapies plus radiotherapy in glioblastoma: the phase 1/2a N2M2 umbrella trial.
    Wolfgang Wick, Lisa-Marie Lanz, Antje Wick, Inga Harting, Susan Dettmer, Abigail K Suwala, Ralf Ketter, Ghazaleh Tabatabai, Corinna Seliger, Martin Glas, Michael C Burger, Marco Timmer, Florian A Ringel, Iris Mildenberger, Walter J Schulz-Schaeffer, Frank Winkler, Laila König, Christel Herold-Mende, Andreas Eisenmenger, Stefan M Pfister, Mirjam Renovanz, Martin Bendszus, Felix Sahm, Michael Platten, Tobias Kessler.
      Advances in molecular understanding and diagnostic precision of glioblastoma enable the identification of key genetic alterations in a timely manner and, in principle, allow treatments with targeted compounds based on molecular markers. Here we report the results of the phase 1/2 umbrella trial NCT Neuro Master Match (N2M2), which evaluated targeted treatments in 228 patients with newly diagnosed glioblastoma without O6-methylguanine DNA-methyltransferase promoter hypermethylation. Stratification for treatment was conducted by a trial-specific molecular tumor board across five subtrials, each evaluating a targeted therapy-alectinib, idasanutlin, palbociclib, vismodegib or temsirolimus-selected according to the best-matching molecular alteration. Patients without matching alterations were randomized between subtrials without strong biomarkers using atezolizumab and asunercept, and the standard of care (SOC), temozolomide. All received radiotherapy. The primary endpoints were dose-limiting toxicities (phase 1) and progression-free survival at 6 months (PFS-6; phase 2). Secondary endpoints included safety and tolerability, as well as overall survival (OS). The subtrials for alectinib and vismodegib did not open as they did not have matching patients. The idasanutlin subtrial (n = 9) was terminated early at the discretion of the manufacturing company. The temsirolimus subtrial (n = 46) demonstrated a PFS-6 of 39.1% and median OS of 15.4 months in patients with activated mammalian target of rapamycin (mTOR) signaling compared to a PFS-6 at 18.5% in the SOC group (n = 54), meeting the primary endpoint. The atezolizumab (n = 42), asunercept (n = 26) and palbociclib (n = 41) subtrials did not meet the primary endpoint for efficacy. The safety signals of N2M2 match prior experiences with the drugs in quality and quantity; no relevant negative interaction with the parallel radiotherapy was noted. The results of the N2M2 trial support further investigation of temsirolimus in addition to radiotherapy in patients with newly diagnosed glioblastoma with activated mTOR signaling. ClinicalTrials.gov registration: NCT03158389 .
    DOI:  https://doi.org/10.1038/s41591-025-03928-9
  10. Neuro Oncol. 2025 Sep 01. pii: noaf190. [Epub ahead of print]
    Spatial profiling of longitudinal glioblastoma reveals consistent changes in cellular architecture, post-treatment.
    Shoaib Ajaib, Joshua Winter-Luke, Richard J Digby, Steven Pollock, Gemma Hemmings, Arief Gusnanto, Aruna Chakrabarty, Azzam Ismail, Erica Wilson, Bethany Hunter, Andrew Filby, David McDonald, Asa A Brockman, Rebecca A Ihrie, Lucy F Stead.
       BACKGROUND: Glioblastoma (GBM), the most aggressive adult brain cancer, comprises a complex tumour microenvironment (TME) with diverse cellular interactions that drive progression and pathobiology. The aim of this study was to understand how these spatial patterns and interactions evolve with treatment.
    METHODS: To explore these relationships, we employed imaging mass cytometry to measure the expression of 34 protein markers, enabling the identification of GBM-specific cell types and their interactions at single-cell protein level in paired primary (pre-treatment) and recurrent (post-treatment) GBM samples from five patients.
    RESULTS: We find a significant post-treatment increase in normal brain cells alongside a reduction in vascular cells. Moreover, despite minimal overall change in cellular diversity, interactions among astrocytes, oligodendrocytes, and vascular cells increase post-treatment, suggesting reorganisation of the TME. The GBM TME cells form spatially organized layers driven by hypoxia pre-treatment, but this influence diminishes post-treatment, giving way to less organised layers with organisation driven by reactive astrocytes and lymphocytes.
    CONCLUSIONS: These findings provide insight into treatment-induced shifts in GBM's cellular landscape, highlighting aspects of the evolving TME that appear to facilitate recurrence and are, therefore, potential therapeutic targets.
    Keywords:  GBM; Glioblastoma; IDHwt; IMC; Imaging mass cytometry; TME
    DOI:  https://doi.org/10.1093/neuonc/noaf190
  11. Neuro Oncol. 2025 Aug 28. pii: noaf189. [Epub ahead of print]
    AI-driven WHO 2021 classification of gliomas based only on H&E-stained slides.
    Shubham Innani, W Robert Bell, MacLean P Nasrallah, Bhakti Baheti, Spyridon Bakas.
       BACKGROUND: The WHO 2021 classification criteria for adult diffuse glioma integrate histology with molecular profiling for conclusive diagnosis. Since molecular profiling can be expensive and time-consuming, often necessitating outsourcing or leading to the 'not otherwise specified (NOS) label', this study develops an AI-driven WHO 2021 classification of gliomas solely from H&E whole-slide images (WSIs).
    METHODS: Our pipeline is based on a multi-institutional dataset reclassified per WHO 2021 guidelines. This dataset includes a) Primarily US based TCGA-GBM/TCGA-LGG (n=1,320) for model training, independently evaluated on two hold-out sets, b) Austria-based EBRAINS (n= 794) c) India-based IPD-Brain (n=304). Each WSI undergoes pre-processing followed by quantitative benchmarking across i) eight pathology foundation models, ii) nine aggregation methods, and (iii) 15 combinations of magnification levels through a late fusion approach. Model interpretability conducted through heatmaps highlights distinct, identifiable morphology features.
    RESULTS: Our best-performing combination of FM, AM, and multi-magnification achieved an AUC of 97.95% on the training cohort, 96.30% on EBRAINS (set 1), and 92.61% on IPD (set 2). The results yield the following key insights: (1) domain-specific FMs outperform ImageNet-based models, (2) AMs while theoretically promising yield larger performance improvements when used with ImageNet based feature extractor rather than FMs, and (3) Fusion of multiple magnifications adds value in performance.
    CONCLUSION: Determining glioma diagnosis directly from H&E slides can obviate the need for molecular profiling, expedite conclusive diagnosis, and, hence, clinical decision-making. These findings motivate the development of advanced domain-relevant foundation models and the design of more adaptable slide-level aggregation techniques.
    Keywords:  computational pathology; embedding aggregation; foundation models; glioma; multi-magnification
    DOI:  https://doi.org/10.1093/neuonc/noaf189
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