bims-malgli 2025-11-30 papers

bims-malgli

Biomed News

on Biology of malignant gliomas

Issue of 2025–11–30
sixteen papers selected by
Oltea Sampetrean, Keio University

Reprogramming the Immune Suppressive Tumor Microenvironment in Glioma Enhances the Efficacy of Immune-Mediated Gene Therapy.
Microbubble-enhanced transcranial focused ultrasound with temozolomide for patients with high-grade glioma (BT008NA): a multicentre, open-label, phase 1/2 trial.
Adaptive nuclear GTP synthesis promotes glioblastoma treatment resistance and is a targetable vulnerability in patients.
Increased neural excitability and glioma synaptic activity drives glioma proliferation in human cortex.
Human RAP2A homolog of the Drosophila asymmetric cell division regulator Rap2l targets the stemness of glioblastoma stem cells.
The glymphatic system and glioblastoma.
Spatial transcriptomics of glioblastoma defines biologically and clinically significant reprogramming patterns across unique spatial microenvironments.
USP14-mediated stabilization of ACTN1 maintains mesenchymal characteristics in glioblastoma.
Post-Chemoradiation Lymphopenia and Baseline Eosinophil Counts as Prognostic Markers in Glioblastoma.
Virtual Clinical Trials of BMP4 Differentiation Therapy: Digital Twins to Aid Successful Glioblastoma Trial Design.
Region-specific human brain organoids reveal synaptic and cell state drivers of glioblastoma invasion.
Daily locomotor activity declines with tumor growth and disease progression in glioblastoma.
Characterization of quiescent subpopulations and proliferative compartments in glioblastoma.
A prognostic classification system for extent of resection in IDH-mutant grade 2 glioma: an international, multicentre, retrospective cohort study with external validation by the RANO resect group.
Focused ultrasound treatments could increase survival in individuals with glioma.
AI-augmented intraoperative decision-making workflows in diffuse midline glioma biopsy using cryosection pathology.

bioRxiv. 2025 Nov 13. pii: 2025.11.11.687828. [Epub ahead of print]

Reprogramming the Immune Suppressive Tumor Microenvironment in Glioma Enhances the Efficacy of Immune-Mediated Gene Therapy.

Brandon L McClellan, Jorge A Peña Agudelo, Anzar A Mujeeb, Ali A Dabaja, Ziwen Zhu, Sadhakshi Raghuram, Maria Luisa Varela, Claire Tronrud, Kaushik Banerjee, Abraham Wei, Cecilia Calatroni, Lucia H Zhang, Lissa Cruz Romero, Paul Oh, Mahmoud S Alghamri, Andrew Robbins, Matthew D Perricone, Ying Wang, Brian Shay, Peter Sajjakulnukit, Costas A Lyssiotis, Joshua D Welch, Anna Schwendeman, Pedro R Lowenstein, Maria G Castro.

Gliomas account for ~80% of primary malignant brain tumors. Many CNS WHO grade 2-3 and some grade 4 gliomas harbor mutant isocitrate dehydrogenase 1 (mIDH1), which causes a gain of function mutation (IDH1 R132H) leading to the production of 2-hydroxyglutarate (2HG). Mutant IDH1-induced 2HG, through epigenetic reprogramming elicits an immune-permissive tumor microenvironment (TME). An immunosuppressive mechanism in the glioma TME involves adenosine production via the ectoenzyme CD73. This study investigates mIDH1's influence on CD73 expression and adenosine levels. We demonstrate that mIDH1 glioma cells exhibit reduced CD73 expression, driven by DNA hypermethylation, leading to reduced adenosine levels. Since wtIDH1 gliomas have high CD73 expression, we evaluated CD73 blockade as an immunotherapy target. We show that CD73 inhibition used as monotherapy, did not improve survival in wtIDH1 glioma-bearing mice. However, when combined with immune-stimulatory Ad-TK (adenoviral vectors encoding herpes simplex virus thymidine kinase) and Ad-Flt3L (adenoviral vectors encoding FMS-like tyrosine kinase 3 ligand) gene therapy, CD73 blockade significantly enhanced therapeutic efficacy and increased anti-glioma effector T cell activity. These findings reveal that CD73 inhibition used in combination with immune stimulatory Ad-TK/Ad-Flt3L gene therapy may be an effective treatment for wtIDH1 gliomas, which could be readily translated to the clinical arena.

DOI: https://doi.org/10.1101/2025.11.11.687828
Lancet Oncol. 2025 Dec;pii: S1470-2045(25)00492-9. [Epub ahead of print]26(12): 1651-1664

Microbubble-enhanced transcranial focused ultrasound with temozolomide for patients with high-grade glioma (BT008NA): a multicentre, open-label, phase 1/2 trial.

Graeme F Woodworth, Pavlos Anastasiadis, Ahmad Ozair, Jeremi Chabros, Chetan Bettegowda, Chixiang Chen, Jakob V E Gerstl, Christopher Douville, Rania A Mekary, Timothy R Smith, Ying Meng, Cynthia Hawkins, Christopher B Pople, Agessandro Abrahao, Maheleth Llinas, Chinthaka Heyn, Adomas Bunevicius, Ali R Rezai, Anna J S Ball, Kaitlyn Henry, Arjun Sahgal, Erickson Torio, Haoyu Ren, Haroon Ahmad, Harshit Arora, Howard Eisenberg, James Perry, Jeffrey S Carpenter, Kullervo Hynynen, Lily C Pham, Mary Beth Anketell, Mary Jane Lim-Fat, Zhiyuan Xu, Christopher P Cifarelli, Jason P Sheehan, Nathan J McDannold, Dheeraj Gandhi, Alexandra J Golby, Nir Lipsman.

BACKGROUND: Brain-infiltrating tumour cells from high-grade glioma remain shielded from drug treatments by the blood-brain barrier, leading to inevitable recurrence. Microbubble-enhanced transcranial focused ultrasound (MB-FUS) enables controlled blood-brain barrier opening (BBBO), permitting localised drug delivery. We aimed to assess safety and feasibility of MB-FUS plus standard-of-care chemotherapy for individuals with high-grade glioma.
METHODS: BT008NA was an open-label, single-arm, phase 1/2 trial conducted at five sites in the USA and Canada (part of the ReFOCUSED Consortium). Key eligibility criteria were participants with newly diagnosed high-grade glioma (glioblastoma as per WHO 2016 classification), aged 18-80 years, with normal organ function, a baseline Karnofsky Performance Status score of 70 or higher, who had received maximal safe resection and 6-week chemoradiotherapy and were to start standard-of-care monthly adjuvant temozolomide chemotherapy (150 mg/m2 of body surface area). MRI-guided, 220 kHz transcranial MB-FUS treatments were delivered in periresectional (tumour-infiltrative) regions, on any of the first 3 days of a 28-day temozolomide cycle, for up to six cycles. Primary outcomes were safety (adverse events) and feasibility (BBBO: new contrast enhancement on post-procedure T1-weighted MRI). Protocol-prespecified secondary outcomes were overall survival and progression-free survival. Analyses were done in the intention-to-treat population. This trial is registered at ClinicalTrials.gov, NCT03551249 (USA) and NCT03616860 (Canada), and is closed to enrolment.
FINDINGS: Between Oct 16, 2018, and March 9, 2022, we enrolled 34 participants, all evaluable for prespecified primary and secondary endpoints, with a mean age of 51·5 years (SD 13·0) and median follow-up 44·5 months (95% CI 34·9-57·3). By self-reporting, 18 (53%) participants were female and 16 (47%) male, 28 (82%) were White, and 34 (100%) were non-Hispanic. 176 adverse events were captured: 54 (31%) chemotherapy-related, 10 (6%) disease-related, 87 (49%) related to undergoing MB-FUS (40 [46%] grade 1, 46 [53%] grade 2, and one [1%] grade 3), and 25 (14%) unrelated. Two (1%) of the adverse events were grade 5 (disease-related deaths), three (2%) grade 4 (temozolomide-related haematological abnormalities), and eight (5%) grade 3 (three [2%] temozolomide-related, one [1%] MB-FUS-related, three [2%] disease-related, and one [1%] unrelated); these occurred across seven (21%) of 34 participants. No treatment-related deaths occurred during the trial. BBBO was visualised in all treatments. Median overall survival was 31·3 months (95% CI 21·1-not reached) and median progression-free survival was 13·5 months (9·9-26·9) with patient-specific disease courses found concordant with trajectories of MB-FUS-enriched plasma cell-free DNA.
INTERPRETATION: MB-FUS plus temozolomide is a safe combinatorial therapeutic approach for individuals with high-grade glioma, with the potential to improve survival and enable non-invasive plasma biomarker-based disease surveillance (sono-liquid biopsy), warranting randomised controlled trials.
FUNDING: National Institutes of Health and Insightec.

DOI: https://doi.org/10.1016/S1470-2045(25)00492-9
medRxiv. 2025 Nov 13. pii: 2025.11.11.25340023. [Epub ahead of print]

Adaptive nuclear GTP synthesis promotes glioblastoma treatment resistance and is a targetable vulnerability in patients.

Andrew J Scott, Ningning Liang, Wajd N Al-Holou, Jie Xu, Alexandra O'Brien, Angelica Lin, Vidhi Pareek, Zhou Sha, Zitong Zhao, John Z Yang, Annabel Yang, Ayesha U Kothari, Kari Wilder-Romans, Zhe Wu, Jiane Feng, Navyateja Korimerla, Ameer Elaimy, Sravya Palavalasa, Jiali Chen, Lu Wang, Li Zhang, Anthony C Andren, Peter Sajjakulnukit, Bernard Marini, Jason A Heth, Meredith A Morgan, Theodore S Lawrence, Stephen J Benkovic, Deepak Nagrath, Sriram Chandrasekaran, Nathan R Qi, Duxin Sun, Bo Wen, Manjunath P Pai, Nathan Clarke, Krithika Suresh, Yoshie Umemura, Costas A Lyssiotis, Weihua Zhou, Daniel R Wahl.

Glioblastoma (GBM), the most lethal of all brain cancers, resists therapy by rewiring metabolism and relying on GTP signaling to promote DNA repair and radiation therapy (RT) resistance. How GBM modulates GTP levels for this signaling in response to RT-induced DNA damage, and the therapeutic tractability of this metabolic activity in the context of standard-of-care chemoradiation therapy, remain unaddressed. Here, we identify acute changes in glioma metabolism within hours of RT, including an acute post-RT rewiring of guanylate synthesis driven by nuclear translocation of the rate-limiting de novo guanylate synthesis enzyme IMPDH1. This subcellular IMPDH1 re-localization and nuclear GTP accumulation are dependent on the DNA damage signal kinase DNA-PK. Targeting intracranial GTP synthesis with the FDA-approved inhibitor mycophenolate mofetil (MMF) slows repair of DNA damage and extends survival of orthotopic murine models treated with combined RT and temozolomide. Extending our findings to humans, we performed a phase 0 clinical trial revealing that oral MMF administration leads to active intracranial drug concentrations, with target engagement indicated by reversal of IMPDH upstream and downstream metabolites in recurrent GBM tumors. Together, these findings implicate IMPDH as a potential metabolic target in GBM whose pharmacological inhibition is feasible and could complement standard-of-care chemoradiation therapy.

DOI: https://doi.org/10.1101/2025.11.11.25340023
Nat Neurosci. 2025 Nov 26.

Increased neural excitability and glioma synaptic activity drives glioma proliferation in human cortex.

Heidi McAlpine, Marius Rosier, Jordan Rozario, Xiaoyu Wang, Verena C Wimmer, Robertas Guzulaitis, Hefei Guan, Yi Hu, Leonid Chirlov, Christian Davey, Sue Finch, Katharine Jann Drummond, Lucy Maree Palmer.

Adult gliomas are incurable primary brain cancers that infiltrate healthy brain and incorporate into neural networks. Gliomas can be classified as low grade or high grade based on histopathological and molecular features, which broadly predicts their aggressiveness. Here we performed patch-clamp electrophysiological recordings from pyramidal neurons and glioma cells from individuals with either low- or high-grade glioma. We find that the biophysical properties of human pyramidal neurons within glioma-infiltrated cortex differ according to tumor grade, with neurons from high-grade glioma being more excitable than those from low-grade glioma. Additionally, glioma cells within high-grade tumors have smaller, longer synaptic responses. Increased neuron-glioma network activity within human high-grade tumor tissue leads to increased glioma proliferation, suggesting that the hyperexcitability of pyramidal neurons in human high-grade glioma may drive tumor growth. Combined, our findings illustrate that high- and low-grade glioma differentially hijack neural networks.

DOI: https://doi.org/10.1038/s41593-025-02149-0
Elife. 2025 Nov 28. pii: RP105690. [Epub ahead of print]14

Human RAP2A homolog of the Drosophila asymmetric cell division regulator Rap2l targets the stemness of glioblastoma stem cells.

Maribel Franco, Ricardo Gargini, Víctor M Barberá, Daniel Becerra, Miguel Saceda, Ana Carmena.

  Asymmetric cell division (ACD) is a fundamental process to balance cell proliferation and differentiation during development and in the adult. Cancer stem cells (CSCs), a very small but highly malignant population within many human tumors, are able to provide differentiated progeny by ACD that contribute to the intratumoral heterogeneity, as well as to proliferate without control by symmetric, self-renewing divisions. Thus, ACD dysregulation in CSCs could trigger cancer progression. Here, we consistently find low expression levels of RAP2A, the human homolog of the Drosophila ACD regulator Rap2l, in glioblastoma (GBM) patient samples, and observe that scarce levels of RAP2A are associated with poor clinical prognosis in GBM. Additionally, we show that restitution of RAP2A in GBM neurosphere cultures increases the ACD of glioblastoma stem cells (GSCs), decreasing their proliferation and expression of stem cell markers. Our results support that ACD failures in GSCs increase their spread and ACD amendment could contribute to reduce the expansion of GBM.

Keywords:  D. melanogaster; Drosophila; asymmetric stem cell division; cancer biology; cell biology; glioblastoma neurosphere cultures; glioblastoma stem cells; human; human RAP2A

DOI:  https://doi.org/10.7554/eLife.105690
Brain. 2025 Nov 28. pii: awaf449. [Epub ahead of print]

The glymphatic system and glioblastoma.

Andrea Soumbasis, Aito Ueno, David Elliott, Sanju Lama, Sarah Edwards, Yves P Starreveld, Yunyan Zhang, Paolo Federico, Garnette R Sutherland, Pierre LeVan, Candice C Poon.

  The discovery of the glymphatic system and meningeal lymphatic vessels revolutionized the understanding of brain waste clearance. These findings challenged the long-held notion of central nervous system (CNS) immune privilege and provided insights into how the brain maintains homeostasis despite lacking conventional lymphatic drainage. However, the impact of pathological conditions, particularly CNS cancers, on the glymphatic system and vice versa remains underexplored. Glioblastoma (GBM) is the most common and aggressive primary adult CNS cancer. Its presence results in glymphatic dysfunction with significant clinical implications. Recent studies suggest that the glymphatic system interacts with GBM to influence immunity, drug delivery, fluid regulation, and tumor progression, stressing its significant role in GBM biology and potentially treatment response. This review highlights the evidence for glymphatic dysfunction in GBM and its consequences. Furthermore, we discuss the potential to harness the power of the glymphatic system to improve patient outcomes in this terrible disease.

Keywords:  glioblastoma; glioma; glymphatic system; immunology; meningeal lymphatic system

DOI:  https://doi.org/10.1093/brain/awaf449
bioRxiv. 2025 Oct 26. pii: 2025.10.17.683110. [Epub ahead of print]

Spatial transcriptomics of glioblastoma defines biologically and clinically significant reprogramming patterns across unique spatial microenvironments.

Visweswaran Ravikumar, Avery Maddox, Reva Kulkarni, Arvind Rao, Wajd N Al-Holou.

Glioblastoma (GBM) is the most common and lethal primary malignant tumor of the central nervous system. Advances in therapy are hindered by the complex intratumoral heterogeneity of GBM, where distinct malignant and non-malignant cellular states and interactions exist in spatially defined niches of the tumor microenvironment (TME), shaping both tumor behavior and treatment response. In this work, we define GBM biological reprogramming, TME recomposition, and cell-cell interactions in relation to spatially well defined Ivy Glioblastoma Atlas Project regions. Further, we apply a novel spatially informed approach to integrate biological reprogramming, as identified through gene co-expression network modules, with specific changes in cell-cell communications. Our results validate prior findings and offer novel insights into the spatial patterning of transcription factor regulation, cellular interactions, and biological pathway activity, in addition to informing rational combination therapies targeting spatial niche specific vulnerabilities. In addition, our work contributes a novel Visium spatial transcriptomics dataset of 14 samples for use by the GBM research community.

DOI: https://doi.org/10.1101/2025.10.17.683110
Commun Biol. 2025 Nov 25. 8(1): 1680

USP14-mediated stabilization of ACTN1 maintains mesenchymal characteristics in glioblastoma.

Wenjin Qiu, Xueping Shi, Ruting Wei, Jiaquan Song, Yuanguo Ling, Yunjia Hu, Shibin Song, Yimin Chen, Hua Yang, Peng Luo, Liangzhao Chu.

Glioblastoma (GBM) is a highly aggressive primary brain tumor with a dismal prognosis, particularly in its mesenchymal (MES) subtype, which correlates strongly with poor survival. Despite this, the mechanisms preserving MES identity remain poorly understood. Here, we show that alpha-actinin 1 (ACTN1) is upregulated in MES GBM and drives proneural-to-mesenchymal transition (PMT). Using patient samples and multiple GBM cell lines, we find that ACTN1 overexpression promotes proliferation, invasion, and tumorigenesis, while its silencing diminishes these malignant traits and shifts gene expression away from MES markers. Mechanistically, we identify ubiquitin-specific peptidase 14 (USP14) as a pivotal deubiquitinase (DUB) that stabilizes ACTN1 by removing its ubiquitin chains. Pharmacological inhibition of USP14 with IU1 reduces ACTN1 protein levels, impairs MES-associated phenotypes, and suppresses tumor progression in vitro and in intracranial xenograft models. Clinically, elevated USP14 and ACTN1 expression correlates with poorer survival in GBM patients, highlighting the USP14-ACTN1 axis as a key driver of PMT and a promising therapeutic target for this devastating disease.

DOI: https://doi.org/10.1038/s42003-025-09083-8
Res Sq. 2025 Oct 12. pii: rs.3.rs-7715242. [Epub ahead of print]

Post-Chemoradiation Lymphopenia and Baseline Eosinophil Counts as Prognostic Markers in Glioblastoma.

Eric Giannaris, Geoffrey Sedor, Catherine S Spina, Kristin Hsieh, Carl Elliston, Simon K Cheng, Fabio M Iwamoto, Guy M McKhann, Michael B Sisti, Jeffrey N Bruce, Tony J C Wang, Matthew Gallitto.

Purpose To evaluate whether post-treatment lymphopenia and white-cell differentials predict overall survival (OS) in glioblastoma (GBM). Methods We retrospectively analyzed 93 GBM patients treated with standard surgery, radiotherapy (60 Gy in 30 fractions), and temozolomide. Clinical data (age, Karnofsky performance status, extent of resection, MGMT methylation, corticosteroid use, dose metrics) and hematologic indices (absolute lymphocyte count (ALC), neutrophil-to-lymphocyte ratio (NLR), absolute eosinophil (AEC) and basophil counts, etc.) were collected at baseline and up to 3 months post-chemoradiation. Results Median OS in our cohort was 24.7 months (95% CI, 20.8-35.0). On univariate analysis, ALC < 0.75 ×10³/µL at 3 months was associated with shorter OS (HR 1.88; p = 0.042), and higher AEC correlated with improved OS at baseline (HR 0.71; p = 0.022) and at 1-2 months (HR 0.44 and 0.57; p = 0.046 and 0.016). In the combined multivariable model-controlling for age, extent of resection, MGMT status, steroid usage and dose metrics-baseline AEC remained independently prognostic (aHR 0.57; p = 0.016), whereas the association for 3-month ALC < 0.75 ×10³/µL attenuated (aHR 1.27; p = 0.49). Conclusions Baseline eosinophils were independently associated with improved survival, while post-treatment lymphopenia was adverse only on univariate analysis. Such findings highlight the importance of host immunity and baseline eosinophils as a potential prognostic marker of OS in GBM and warrant larger, prospective studies on lymphocyte-sparing treatment strategies and prognostic marker validation.

DOI: https://doi.org/10.21203/rs.3.rs-7715242/v1
bioRxiv. 2025 Oct 06. pii: 2024.08.22.609156. [Epub ahead of print]

Virtual Clinical Trials of BMP4 Differentiation Therapy: Digital Twins to Aid Successful Glioblastoma Trial Design.

Nicholas Harbour, Lee Curtin, Loizos Michaelides, Matthew E Hubbard, Pamela Jackson, Vinitha Rani, Rajappa S Kenchappa, Virginea de Araujo Farias, Anna Carrano, Markus R Owen, Alfredo Quinones-Hinojosa, Kristin R Swanson.

Glioma stem cells (GSCs) are considered a major driver of glioblastoma (GBM) progression and are highly resistant to standard cytotoxic treatments. BMP4 has been shown to drive differentiation of GSCs, increase sensitivity to radiotherapy, slow growth and increase survival times in animal models. To assess the potential of BMP4 as a differentiation therapy, we develop a mathematical model that describes the growth of a GBM tumor via a hierarchy of GSCs, progenitor cells and terminally differentiated cells. We parametrize our model using experimental data from twelve patient-derived GSC lines, on which we measured response to radiotherapy and population growth with and without exposure to BMP4. Cell lines were typically more sensitive to radiotherapy after two days of BMP4 treatment but population growth can either increase or decrease after seven days of exposure to BMP4. To identify key parameters that drive successful treatment we perform global sensitivity analysis which identifies key parameters for BMP4 efficacy including proliferation rate and self-renewal sensitivity of GSCs. We then compare two treatment schedules: a single dose of BMP4 at resection and continuous delivery of BMP4 from resection till the end of radiotherapy. Due to the short half-life of BMP4 and its synergy with radiotherapy, continuous delivery of BMP4 during radiotherapy is more effective than a single dose prior to radiotherapy. We then perform a series of virtual clinical trials, stratified by tumor proliferation rate and GSC self-renewal sensitivity, which allows us to estimate the probability of observing a successful early-phase clinical trial for various virtual patient cohorts. We find that trials that selected the subset of patients with more proliferative GBMs were more likely to lead to significant improvements in survival.
Significance: Targeting glioma stem cells with BMP4 provides a novel opportunity to shift the complex cellular ecosystem of gliomas to enhance treatment efficacy. Mathematical modelling can facilitate optimal patient tumor feature selection when designing successful clinical trials.

DOI: https://doi.org/10.1101/2024.08.22.609156
bioRxiv. 2025 Oct 15. pii: 2025.10.15.682580. [Epub ahead of print]

Region-specific human brain organoids reveal synaptic and cell state drivers of glioblastoma invasion.

Tarun N Bhatia, Saisrinidhi Ganta, Mostafa Meselhe, Caitlin Sojka, Antoni Martija, Lisa Nieland, Uriel Rufen-Blanchette, Anson Sing, Alexia King, Brain Organoid Hub, Aparna Bhaduri, Kimberly Hoang, Edjah Nduom, Renee D Read, Jeffrey Olson, Steven A Sloan.

Glioblastoma (GBM) is a highly heterogenous and malignant brain tumor, in part because it disrupts normal brain circuits to fuel its own growth and invasion. Thus, there is a need to identify the molecular features of invasive GBM cells and their regulators in the neural microenvironment. To address this in a fully human model, we engrafted patient-derived GBM cells (total n= 15 independent samples) from three sources- fresh neurosurgical resections, cell lines, and whole GBM organoids-into human induced pluripotent stem cell-derived organoids patterned to forebrain, midbrain, and spinal cord identities. GBM cells from all sources infiltrated brain organoids within 2 days post-engraftment, reaching maximal invasion by day 14. Across organoids of distinct spatial and maturational milieu, GBM cells showed a consistent reduction in astrocyte-like states and an enrichment in neuron/glia progenitor-like (NPC-like) states. These NPC-like GBM cells expressed neuronal and synaptic machinery, and tumors enriched in this transcriptomic state prior to engraftment achieved greater organoid coverage, suggesting enhanced infiltration and synaptic integration of this GBM cell type. Although GBM cell states converged across organoid types after engraftment, infiltration was greater in the forebrain than spinal cord. This is likely reflective of synaptic input from deep-layer TBR1⁺ excitatory neurons in the forebrain, as demonstrated by a combination of rabies-based monosynaptic tracing and single-cell transcriptomics. In contrast, inhibitory neurons were the predominant synaptic partners of GBM in the spinal cord. Together, this fully human model of the neural-GBM connectome reveals how neuron-like GBM states and regionally distinct synaptic inputs cooperatively shape tumor invasion.

DOI: https://doi.org/10.1101/2025.10.15.682580
JCI Insight. 2025 Nov 25. pii: e194582. [Epub ahead of print]

Daily locomotor activity declines with tumor growth and disease progression in glioblastoma.

Maria F Gonzalez-Aponte, Sofia V Salvatore, Anna R Damato, Ruth Gn Katumba, Grayson R Talcott, Omar H Butt, Jian L Campian, Jingqin Luo, Joshua B Rubin, Olivia J Walch, Erik D Herzog.

  Glioblastoma (GBM) is an aggressive brain tumor that often progresses despite resection and treatment. Timely and continuous assessment of GBM progression is critical to expedite secondary surgery or enrollment in clinical trials. However, current progression detection requires costly and specialized magnetic resonance imaging (MRI), which, in the absence of new symptoms or signs, is usually scheduled every 2 to 3 months. Here, we hypothesized that changes in daily activity associate with GBM growth and disease progression. We found that wheel-running activity in GBM-bearing mice declined as tumors grew, and preceded weight loss and circadian breakdown by over a week. Temozolomide treatment in the morning, but not evening, significantly reduced tumor size and restored daily locomotion in mice. In a pilot study of six GBM patients wearing an actigraphy watch, wrist movement provided a feasible and continuous longitudinal indicator of daily activity with one-minute resolution. Following tumor resection and radiation, daily activity declined in two patients 19 and 55 days before detection of progression by MRI, but did not change for the four patients with stable disease. These results suggest that daily activity tracking using wearable devices may serve as a real-time indicator and potential monitoring tool for GBM progression and treatment efficacy.

Keywords:  Behavior; Brain cancer; Clinical Research; Clinical practice; Neuroscience; Oncology

DOI:  https://doi.org/10.1172/jci.insight.194582
bioRxiv. 2025 Oct 06. pii: 2025.10.03.680278. [Epub ahead of print]

Characterization of quiescent subpopulations and proliferative compartments in glioblastoma.

Anca B Mihalas, Kelly Mitchell, Sonali Arora, Samantha A O'Connor, Anoop P Patel, Christopher L Plaisier, Patrick J Paddison.

Glioblastoma (GBM) quiescent (Q) cell populations are hypothesized to contain cancer stem-like cells (CSC) that drive tumor growth, cellular heterogeneity, and recurrence. However, GBM tumors do not neatly resolve into developmental hierarchies and Q stem-like activities are difficult to assess. Here, we evaluated tumor Q subpopulations in patient-derived GBM xenograft tumors using live cell reporters, DNA label retention assays, and single cell genomics. Compared to adult neural stems cells (NSCs), GBM Q populations contain hybrid transcriptional states composed of networks found in both dormant and activated adult NSCs, resulting in constitutive expression of key Q egress transcription factors and their targets (e.g., AP-1 and CCND1/2 ). As a result, even the longest Q-residing cells (∼12 days) in xenograft tumors continuously cycle and fail to enter dormant Q states. We provide evidence and hypothesize that transient Q states in primary tumors arise as part of distinct proliferative compartments rather than deterministic developmental hierarchies driven by CSC activity. We further speculate that increases in basal translation rates drive Q instability in GBM tumors.

DOI: https://doi.org/10.1101/2025.10.03.680278
Lancet Oncol. 2025 Dec;pii: S1470-2045(25)00534-0. [Epub ahead of print]26(12): 1638-1650

A prognostic classification system for extent of resection in IDH-mutant grade 2 glioma: an international, multicentre, retrospective cohort study with external validation by the RANO resect group.

Philipp Karschnia, Jacob S Young, Maarten M J Wijnenga, Tommaso Sciortino, Nico Teske, Alba Corell, Arthur Wagner, Gilbert Youssef, Yae Won Park, Levin Häni, Stephanie T Jünger, Antonio Dono, Felix Ehret, Eduardo E Mendoza Mireles, Nicolas Neidert, Francesco Bruno, Chad A Tuchek, Thijs van der Vaart, Marco Rossi, Marco Conti Nibali, Lorenzo Gay, Alfred Gramelt, Nitin Tandon, Sung Soo Ahn, Jong Hee Chang, Michael Weller, Arnaud J P E Vincent, Roland Goldbrunner, Daniel P Cahill, Raymond Y Huang, Andreas Raabe, Bernhard Meyer, Juergen Beck, Annette M Molinaro, Susan M Chang, Michael A Vogelbaum, Roberta Rudà, Einar O Vik-Mo, Jorg Dietrich, Yoshua Esquenazi, Stefan J Grau, Patrick Y Wen, Asgeir S Jakola, Oliver Schnell, Lorenzo Bello, Martin J van den Bent, Shawn Hervey-Jumper, Mitchel S Berger, Joerg-Christian Tonn.

BACKGROUND: The efficacy of resection in IDH-mutant grade 2 gliomas remain controversial since terminology for the extent of resection has been inconsistently applied across studies. We aimed to establish a standardised classification for the extent of resection and assess the association between supramaximal resection and survival across molecular subtypes.
METHODS: In this international, multicentre, retrospective study, patients aged 18 years and older with newly diagnosed grade 2 IDH-mutant glioma were identified from institutional databases across 16 centres in the USA, Europe, and Asia between between Sept 1, 1993, and May 10, 2024. We used Cox proportional hazard regressions to analyse the associations between residual tumour and progression-free survival and overall survival. Patients were stratified according to a previously postulated classification system based on residual tumour volume. A cohort of patients from UCSF diagnosed between Feb 16, 1998, and Nov 14, 2017, was used for geographically and institutionally independent external validation.
FINDINGS: We identified 1391 patients with newly diagnosed IDH-mutant grade 2 gliomas, with a median follow-up of 81 months (95% CI 78-85). 728 patients (379 with astrocytoma and 349 with oligodendroglioma) received no first-line treatment beyond surgery, allowing us to study the isolated effects of resection. Patients with maximal T2-fluid attenuated inversion recovery (T2-FLAIR) resection (class 2; 0-5 cm3 remnant) had superior progression-free and overall survival compared with submaximal T2-FLAIR resection (class 3; 5-25 cm3 remnant) or minimal T2-FLAIR resection (class 4; >25 cm3 remnant), with 10-year survival rates of 82% (95% CI 76-87) versus 75% (62-84) versus 48% (29-65; p<0·0001) and 5-year progression-free survival rates of 44% (38-50) versus 25% (16-34) versus 12% (4-24; p<0·0001), respectively. Resection beyond T2-FLAIR borders (class 1) provided survival benefits, with a 10-year survival rate of 98% (95% CI 92-99) and a 5-year progression-free survival rate of 83% (76-88) for supramaximal T2-FLAIR resection (class 1). Associations between survival and extensive resection were evident after 3 years in astrocytomas, whereas survival curves separated after 6-8 years in oligodendrogliomas. The prognostic relevance of the four-tier classification was conserved in multivariable analyses, in 625 patients receiving first-line chemotherapy or radiotherapy (with or without chemotherapy), and in the external UCSF cohort of 381 patients with IDH-mutant grade 2 gliomas.
INTERPRETATION: The proposed RANO classification for extent of resection could serve as a tool for prognostic stratification. Although associations between survival and extensive surgery are evident sooner in patients with astrocytoma, supramaximal resection also translates into survival benefits for patients with oligodendrogliomas.
FUNDING: None.

DOI: https://doi.org/10.1016/S1470-2045(25)00534-0
Lancet Oncol. 2025 Dec;pii: S1470-2045(25)00552-2. [Epub ahead of print]26(12): 1522-1524

Focused ultrasound treatments could increase survival in individuals with glioma.

Antonios N Pouliopoulos.

DOI: https://doi.org/10.1016/S1470-2045(25)00552-2
Nat Commun. 2025 Nov 26.

AI-augmented intraoperative decision-making workflows in diffuse midline glioma biopsy using cryosection pathology.

Yifan Yuan, Qi Yue, Yining Wang, Zunguo Du, Xingfu Wang, Fang Yan, Haixia Cheng, Kaitao Chen, Zanyi Wu, Jianping Song, Chunfeng Song, Bai Lei, Mu Zhou, Mianxin Liu, Ying Mao.

Cryosection pathology is essential for intraoperative diagnosis of diffuse midline gliomas, yet it often leads to diagnostic errors and may prompt unnecessary re-biopsies before completion of the formal molecular assessment. In this study, we propose an AI-augmented framework, CryoAID, for rapid molecular outcome prediction during surgery for patients with diffuse midline glioma. CryoAID integrates a generative model to correct cryosection artefacts and a pathology foundation model to predict molecular statuses directly from cryosection images. We validate CryoAID across multiple cohorts to predict tumoural molecular statuses in the internal (n = 326), external multi-centre (n = 52), and consecutive (n = 68) datasets. In particular, CryoAID accurately predicts major molecular statuses (e.g., ATRX, H3K27M, and TP53) using cryosection images that were previously deemed disqualified for molecular examinations. Beyond tumour cells, CryoAID reveals highly differential clinical features, including glial cell proliferation, abundant cytoplasm, and localised endothelial proliferation. In the retrospective analyses, CryoAID reduces re-biopsy rates by 26.4% and 26.6% in the internal and consecutive datasets, respectively. Our findings demonstrate that the AI-augmented pathology workflow can extract diagnostic value from specimens previously considered non-viable by traditional histopathology. This approach represents a shift towards real-time molecular pathology, potentially reducing re-biopsies and improving diagnostic precision for patients with diffuse midline glioma.

DOI: https://doi.org/10.1038/s41467-025-66853-y