bims-malgli Biomed News
on Biology of malignant gliomas
Issue of 2025–12–07
nine papers selected by
Oltea Sampetrean, Keio University
  1. Pericytes orchestrate a tumor-restraining microenvironment in glioblastoma.
  2. Targeting distinct amino acid metabolic vulnerabilities in IDH-mutant and IDH-wildtype gliomas.
  3. Retargeted oncolytic viruses engineered to remodel the tumor microenvironment for glioblastoma immunotherapy.
  4. IL-8-Induced Tumor Self-Rampart Spatially Confines Oncolytic Virotherapy in Glioblastoma.
  5. Glasdegib in combination with temozolomide and radiotherapy in adult patients with newly diagnosed glioblastoma: the phase Ib/II GEINO 1602 trial.
  6. Multiscale network perspectives on glioma: from tumour biology to symptoms, survival and treatment.
  7. Digital twins for in vivo metabolic flux estimations in patients with brain cancer.
  8. Aberrant neural activity in the peritumoral cortex underlies the progression of tumor-associated seizures.
  9. The development of CAR T cells for patients with CNS malignancies.
  1. Nat Commun. 2025 Dec 04. 16(1): 10918
    Pericytes orchestrate a tumor-restraining microenvironment in glioblastoma.
    Sebastian Braun, Paulina Bolivar, Clara Oudenaarden, Jonas Sjölund, Matteo Bocci, Katja Harbst, Mehrnaz Safaee Talkhoncheh, Bengt Phung, Eugenia Cordero, Rebecca Rosberg, Elinn Johansson, Göran B Jönsson, Alexander Pietras, Kristian Pietras.
      Glioblastoma (GBM) is characterized by fast progression, infiltrative growth pattern, and a high relapse rate. A defining feature of GBM is the existence of spatially and functionally distinct cellular niches, where malignant cells engage in paracrine crosstalk with cell types comprising the tumor microenvironment. Here, we identify pericytes as the most active paracrine signaling hub within the tumor parenchyma. Their depletion through genetic engineering results in accelerated tumor progression and shortened survival. Mechanistic studies reveal that pericyte deficiency remodels the endothelium and impacts the immune cell landscape, exacerbating tumor cell invasion and immune suppression. Specifically, the pericyte-deprived endothelium recruits perivascular, tumor-associated macrophages polarized towards an immune-suppressive phenotype. The recruited macrophages express Hepatocyte Growth Factor, which reinforces activation of its receptor tyrosine kinase MET on GBM cells harboring a pronounced mesenchymal subtype driven by the key phenotypic regulator Fosl1. Indeed, orthotopic implantation of MET-expressing GBM cells corroborates their superior tumor-initiating and invasive capabilities. Thus, pericytes represent critical modulators of GBM development by orchestrating a tumor-suppressive microenvironment, highlighting the importance of their preservation in therapy.
    DOI:  https://doi.org/10.1038/s41467-025-66985-1
  2. Acta Neuropathol Commun. 2025 Nov 29.
    Targeting distinct amino acid metabolic vulnerabilities in IDH-mutant and IDH-wildtype gliomas.
    Shigeo Ohba, Akiyoshi Hirayama, Takao Teranishi, Keisuke Hitachi, Hisateru Yamaguchi, Kazuhiro Murayama, Manabu Natsumeda, Kensuke Tateishi, Kunihiro Tsuchida, Hiroaki Wakimoto, Hideyuki Saya, Russell Pieper, Yuichi Hirose.
      Lower grade gliomas frequently harbor mutations in isocitrate dehydrogenase (IDH), which define biologically distinct tumor subtypes. Although IDH-mutant and IDH-wildtype gliomas share similar histological morphology, they display markedly different metabolic profiles that may be exploited for targeted therapy. In this study, we investigated therapeutic approaches tailored to these metabolic differences. Using capillary electrophoresis-mass spectrometry, we compared the metabolomes of engineered IDH-wildtype and IDH-mutant glioma cell models. IDH-mutant cells exhibited elevated asparagine levels and reduced glutamine and glutamate levels compared with IDH-wildtype cells. These differences were corroborated in vivo by proton magnetic resonance spectroscopy of 130 patients with diffuse gliomas, showing lower glutamine and glutamate in IDH-mutant tumors. Pharmacological depletion of asparagine with L-asparaginase, which converts asparagine to aspartate, preferentially inhibited the growth of IDH-wildtype glioma cells, and this effect was potentiated by inhibition of asparagine synthetase. In contrast, inhibition of glutamate dehydrogenase 1 (GLUD1), the enzyme catalyzing the conversion of glutamate to α-ketoglutarate, selectively suppressed proliferation of IDH-mutant glioma cells by inducing reactive oxygen species accumulation and apoptosis. In vivo, L-asparaginase suppressed tumor growth in xenografted IDH-wildtype gliomas, whereas GLUD1 inhibition significantly reduced tumor growth in IDH-mutant glioma xenografts. These findings reveal distinct amino acid metabolic vulnerabilities defined by IDH mutation status and identify L-asparaginase and GLUD1 inhibition (via R162) as promising, mutation-specific therapeutic strategies. L-asparaginase demonstrated potent antitumor activity against IDH-wildtype gliomas, while GLUD1 inhibition selectively suppressed IDH-mutant gliomas both in vitro and in vivo. These results highlight the clinical potential of targeting amino acid metabolism in gliomas and provide a strong rationale for translating these mutation-specific approaches into future clinical trials.
    Keywords:  Asparagine; Cancer metabolism; Glioma; Glutaminolysis; Isocitrate dehydrogenase
    DOI:  https://doi.org/10.1186/s40478-025-02193-8
  3. Nat Cancer. 2025 Dec 04.
    Retargeted oncolytic viruses engineered to remodel the tumor microenvironment for glioblastoma immunotherapy.
    Federico Giovannoni, Craig A Strathdee, Camilo Faust Akl, Brian M Andersen, Zhaorong Li, Hong-Gyun Lee, María Florencia Torti, Joseph M Rone, Pere Duart-Abadia, Martina Molgora, Linxing Kong, Michael Floyd, Jian Teng, Yulia Gyulakian, Peter Grezsik, Terry Farkaly, Agnieszka Denslow, Sonia Feau, Irene Rodriguez-Sanchez, Judith Jacques, Marco Colonna, Edward M Kennedy, Tooba Cheema, Lorena Lerner, Christophe Quéva, Francisco J Quintana.
      Glioblastoma (GBM) is an aggressive, immunotherapy-resistant brain tumor. Here, we engineered an oncolytic virus platform based on herpes simplex virus 1 for GBM viroimmunotherapy. We mutated the highly cytopathic MacIntyre strain to increase spread and oncolytic activity, limit genetic drift, prevent neuron infection and enable PET tracing. We incorporated microRNA target cassettes to attenuate replication in healthy brain cells. Moreover, we engineered the gD envelope protein to specifically target GBM using EGFR-specific or integrin-specific binders. Lastly, we incorporated five immunomodulators to remodel the tumor microenvironment (TME) by locally expressing IL-12, anti-PD1, a bispecific T cell engager, 15-hydroxyprostaglandin dehydrogenase and anti-TREM2 to target T cells and myeloid cells in the GBM TME. A single intratumoral injection increased survival in GBM preclinical models, while promoting tumor-specific T cell, natural killer cell and myeloid cell responses in the TME. In summary, we engineered a retargeted, safe and traceable oncolytic virus with strong cytotoxic and immunostimulatory activities for GBM immunotherapy.
    DOI:  https://doi.org/10.1038/s43018-025-01070-6
  4. Neuro Oncol. 2025 Dec 03. pii: noaf276. [Epub ahead of print]
    IL-8-Induced Tumor Self-Rampart Spatially Confines Oncolytic Virotherapy in Glioblastoma.
    Shan Jiang, Houshi Xu, Maoyuan Sun, Yongfen Xu, Huihui Chai, Zhen Fan, Zhirui Zhou, Beining Liu, Yue Wang, Ruize Zhu, Jiawen Chen, Yun Guan, Xin Wang, Yulai Zeng, Zhen Li, Weiqiu Ping, Yanlin Teng, Songlin Yan, Tianwen Li, Qisheng Tang, Kangjian Zhang, Zanyi Wu, Bojie Yang, Yifang Ping, Liangfu Zhou, Zhifeng Shi.
       BACKGROUND: Oncolytic virotherapy holds promise for glioblastoma, but the intratumoral replication kinetics of oncolytic viruses and resistance mechanisms of tumor cells remain poorly understood, limiting the development of precise combinssation strategies to improve durable efficacy.
    METHODS: Using the translational RESCUE framework that synchronizes clinical trials with patient-derived xenograft (PDX) models, we profiled the replication kinetics of the oncolytic adenovirus YSCH-01 and performed genome-wide CRISPR activation screening to identify key genes restricting sustained viral replication. Through spatial transcriptomics combined with histological analyses, we delineated the spatial determinants that limit viral dissemination following oncolytic virus administration.
    RESULTS: We identified BCL10 as a key suppressor of sustained viral replication. Viral infection activated the BCL10-NF-κB pathway, triggering paracrine secretion of interleukin-8 (IL-8) from infected tumor cells. IL-8 induced senescence and fibrotic remodeling in neighboring uninfected cells, forming a previously unrecognized Tumor Self-Rampart (TSR)-a concentric barrier of senescent and fibrotic tumor cells that spatially confines viral propagation. TSR was validated in both PDX and patient tumors. IL-8 blockade with Reparixin or peri-dosing glucocorticoids effectively disrupted TSR formation, prolonged viral persistence, and enhanced therapeutic efficacy.
    CONCLUSION: Glioblastoma mounts a spatial self-protective defense through IL-8-driven TSR formation that restricts oncolytic virus spread. IL-8 functions as both a pharmacodynamic biomarker and a therapeutic target, and its inhibition provides a rational strategy to overcome resistance and optimize GBM virotherapy.
    Keywords:  CRISPR Screeningss; Glioblastoma; Interleukin-8; Oncolytic Adenovirus; Tumor Self-Rampart
    DOI:  https://doi.org/10.1093/neuonc/noaf276
  5. Nat Commun. 2025 Dec 04.
    Glasdegib in combination with temozolomide and radiotherapy in adult patients with newly diagnosed glioblastoma: the phase Ib/II GEINO 1602 trial.
    María Ángeles Vaz-Salgado, Sonia Del Barco, Juan Manuel Sepúlveda, Miriam Alonso, Estela Pineda, Carmen Balana, María Martínez-García, Regina Gironés.
      The hedgehog pathway is implicated in resistance to anticancer therapies in glioblastoma (GB). GEINO1602 (NCT03466450) phase Ib/II study evaluated the safety and efficacy of glasdegib and the Stupp scheme in newly diagnosed GB. Patients received glasdegib with radiotherapy plus concomitant and 6 cycles of adjuvant temozolomide followed by glasdegib monotherapy. The recommended phase 2 dose was 75 mg/day of glasdegib. The primary endpoint was the 15-months overall survival (OS), with a futility threshold of 60% to consider the trial positive; accrual required 70 evaluable patients. 79 patients were enrolled. The 15 m OS rate was 52.1% (95% CI: 41.7-65.2). At 2 years, 29.2% of the patients were still alive. The median progression-free survival (PFS) was 7.1 months (95% CI: 6.2-8.6). Glasdegib plus chemoradiotherapy show preliminary efficacy. Despite not surpassing the futility threshold, 30% lived at the data cutoff. Translational research will help define the molecular traits of long-term survivors.
    DOI:  https://doi.org/10.1038/s41467-025-66747-z
  6. Nat Rev Neurol. 2025 Dec 05.
    Multiscale network perspectives on glioma: from tumour biology to symptoms, survival and treatment.
    Linda Douw, Jaap C Reijneveld, Ayan S Mandal.
      Adult glioma is associated with a wide range of symptoms and variable survival that are not fully explained by tumour location or subtype. Recent work suggests that the disease may be better understood using a network-based framework, as opposed to more traditional localizationist thinking. In this Review, we describe three major types of network scaffolds relevant in people with glioma: symptom networks, the connectome and tumour biology networks. We summarize current evidence on how symptoms co-occur to form patterns, how gliomas affect structural and functional brain connectivity beyond the lesion and how tumour cells form intricate networks that interact with their surroundings. We then explore the relationships between local and global perspectives within each scaffold, and how these three scaffolds are interrelated, for example, through associations among tumour connectivity, cognitive performance and survival. We examine how current treatments such as surgery, radiotherapy, chemotherapy and anti-seizure medication interact with various network scaffolds. Group-level findings often do not reflect individual variability, and we highlight the need for personalized, longitudinal, multimodal and standardized network studies. Finally, we outline future steps towards integration of these three, and potentially additional network scaffolds, to provide network-informed care to patients with glioma.
    DOI:  https://doi.org/10.1038/s41582-025-01171-x
  7. Cell Metab. 2025 Dec 01. pii: S1550-4131(25)00482-6. [Epub ahead of print]
    Digital twins for in vivo metabolic flux estimations in patients with brain cancer.
    Baharan Meghdadi, Wajd N Al-Holou, Andrew J Scott, Anjali Mittal, Ningning Liang, Palavalasa Sravya, Abhinav Achreja, Alexandra O'Brien, Kathy Do, Zhe Wu, Jiane Feng, Nathan R Qi, Vijay Tarnal, Sriram Venneti, C Ryan Miller, Jann N Sarkaria, Weihua Zhou, Theodore S Lawrence, Costas A Lyssiotis, Daniel R Wahl, Deepak Nagrath.
      Recent advancements in metabolic flux estimations in vivo are limited to preclinical models, primarily due to challenges in tissue sampling, tumor microenvironment (TME) heterogeneity, and non-steady-state conditions. To address these limitations and enable flux estimation in human patients, we developed two machine learning-based frameworks. First, the digital twin framework (DTF) integrates first-principles stoichiometric and isotopic simulations with convolutional neural networks to estimate fluxes in patient bulk samples. Second, the single-cell metabolic flux analysis (13C-scMFA) framework combines patient single-cell RNA sequencing (scRNA-seq) data with 13C-isotope tracing, allowing single-cell-level flux quantification. These studies allow quantification of metabolic activity in neoplastic glioma cells, revealing frequently elevated purine synthesis and serine uptake, compared with non-malignant cells. Our models also identify metabolic heterogeneity among patients and mice with brain cancer, in turn predicting treatment responses to metabolic inhibitors. Our frameworks advance in vivo metabolic flux analysis, may lead to novel metabolic therapies, and identify biomarkers for metabolism-directed therapies in patients.
    Keywords:  (13)C-single-cell metabolic flux analysis; cancer metabolism; glioblastoma; in vivo isotope tracing; in vivo metabolism; machine learning; purine metabolism; scRNA-seq; serine metabolism; tumor microenvironment
    DOI:  https://doi.org/10.1016/j.cmet.2025.10.022
  8. Nat Commun. 2025 Dec 02. 16(1): 10846
    Aberrant neural activity in the peritumoral cortex underlies the progression of tumor-associated seizures.
    Bibi L J Bouwen, Anne Bolleboom, Yuanhong Tang, Zhaofei Yu, Anna van der Stap, Jort A van Rij, Vera van Dis, Clemens M F Dirven, Chris I De Zeeuw, Olaf van Tellingen, Jian K Liu, Arnaud J P E Vincent, Zhenyu Gao.
      Seizures are frequent complications in brain tumor patients, yet the underlying neuronal mechanisms remain poorly defined. Here, we examined pathophysiological alterations in the peritumoral cortex of patients undergoing tumor resection. The synaptic activity, dendritic spine density, and gene expression of peritumoral pyramidal neurons differed significantly between patients with and without seizures. Using an inducible glioma rodent model, we characterized the progression of these alterations and their predictive value for seizure initiation. Computational simulations revealed that human cortical neurons are highly susceptible to synaptic and dendritic perturbations, which induce paroxysmal depolarizing shifts (PDS) in affected networks. Longitudinal analyses post-surgery showed that PDS were detectable prior to seizure onset in a subset of patients and reliably predicted post-resection seizure occurrence. These findings elucidate key neuronal substrates of tumor-associated seizures and suggest PDS as a potential biomarker for seizure risk, offering a foundation for targeted diagnostic and therapeutic strategies.
    DOI:  https://doi.org/10.1038/s41467-025-66226-5
  9. Nat Rev Clin Oncol. 2025 Dec 01.
    The development of CAR T cells for patients with CNS malignancies.
    Zev A Binder, Stephen J Bagley, Jessica B Foster, Donald M O'Rourke.
      Chimeric antigen receptor (CAR) T cells have become standard-of-care therapies for patients with certain relapsed and/or refractory haematological malignancies over the past decade. However, this approach remains largely ineffective in patients with solid tumours, in part owing to limited CAR T cell persistence, the immunosuppressive tumour microenvironment of many solid tumours and limited trafficking of CAR T cells into tumours. Central nervous system (CNS) tumours, many of which are associated with a poor prognosis and require new treatment approaches, present additional challenges such as the presence of the blood-brain barrier as well as concerns over treatment-related neurotoxicities. Despite these difficulties, clinical trials involving both adult and paediatric patients with primary CNS tumours have provided signals of efficacy. In this Review, we discuss completed, ongoing and anticipated trials testing CAR T cells in patients with CNS tumours. We also highlight the most promising preclinical developments that might lead to novel clinical approaches in this area.
    DOI:  https://doi.org/10.1038/s41571-025-01102-1
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