bims-malgli 2026-04-26 papers

bims-malgli

Biomed News

on Biology of malignant gliomas

Issue of 2026–04–26
eight papers selected by
Oltea Sampetrean, Keio University

Glo1 promotes glioma progression by modulating Sox2 transcriptional networks in glioma stem-like cells.
Beyond cell cycle control: CDKN2A loss is associated with altered NAD+ metabolic states and increased sensitivity to NAMPT inhibition in glioblastoma.
Thr3/Ser90 phosphorylation-stabilized S100A8 regulates cholesterol metabolism in glioblastoma stem cells.
Modeling Gliomas with Organoids: Classification, Fidelity, and Guidelines for Translational Neuro-Oncology.
Targeting YRDC blocks codon-biased FABP7 translation and lipid droplet formation to overcome chemoresistance in glioblastoma.
NEU1 Sustains Mitochondria-Lysosome Contacts to Trigger Lysosomal Cu²⁺/Cathepsin Escape and Mitochondrial lysis in Glioblastoma (NeuLysis).
Prospective biopsy-controlled validation of an AI model for predicting glioblastoma infiltration: Results from the SupraGlio trial.
Astrocyte-driven immunosuppression in the brain tumor microenvironment.

Neuro Oncol. 2026 Apr 20. pii: noag090. [Epub ahead of print]

Glo1 promotes glioma progression by modulating Sox2 transcriptional networks in glioma stem-like cells.

Dong-Joo Choi, Yeunjung Ko, Peihao He, Eun-Ah Christine Song, Jong Min Choi, Rachel Naomi Curry, Brittney Lozzi, Yi-Cian Zheng, Katie Lu, Latha Khatri, Ganesh Rao, Benjamin Deneen.

   BACKGROUND: Glioma stem cells (GSCs) contribute to tumor heterogeneity and are resistant to conventional therapies, making them a significant obstacle to achieving long-term treatment success. However, efforts to eliminate GSCs have been hindered by the lack of reliable markers that provide functional insight into these processes. Therefore, identifying GSC-associated markers is critical for understanding glioma tumorigenesis and for developing targeted therapeutic strategies that can effectively suppress tumor progression and recurrence.
METHODS: We employed single-cell transcriptomics, functional genomics, in vitro assays, and preclinical GBM models, including patient-derived xenografts (PDX) and in utero electroporation (IUE)-based models, to investigate the role of Glyoxalase 1 (Glo1) in GSCs and GBM. Manipulation of Glo1 was achieved through genetic overexpression, knockdown, and pharmacological inhibition.
RESULTS: Glo1 was initially identified through integrative single-cell transcriptomic analyses of human and mouse GBM models, where it is enriched in GSC populations defined by stemness markers. Genetic manipulation of Glo1 indicates that it promotes GSC proliferation and tumor progression, while also being associated with poor prognosis. In addition, pharmacological inhibition of Glo1 significantly reduced GSC viability and tumor growth, and prolonged survival in both PDX and IUE-GBM models. Mechanistically, Glo1 modulation disrupted transcriptional programs associated with GSC maintenance, in part by modulating Sox2 activity.
CONCLUSIONS: These findings demonstrate Glo1 as a key regulator of GSC biology and highlight its potential as a therapeutic target for GSC-directed intervention in GBM. Targeting Glo1 may offer a novel strategy to impair GSC-driven tumor progression and improve GBM treatment outcomes.

Keywords:  Glyoxalase 1; Sox2; glioblastoma; glioma stem-like cells; transcriptional network

DOI:  https://doi.org/10.1093/neuonc/noag090
Neurooncol Adv. 2026 Jan-Dec;8(1):8(1): vdag088

Beyond cell cycle control: CDKN2A loss is associated with altered NAD+ metabolic states and increased sensitivity to NAMPT inhibition in glioblastoma.

Swati Dubey, Guanqiao Yu, Ryana Aboul-Hosn, Christopher Tse, David A Nathanson, Albert Lai, Keith Vossel, Fausto J Rodriguez.

  While CDKN2A loss is classically associated with cell cycle deregulation through the p16-Cdk4-Rb axis, our findings suggest an additional layer of metabolic vulnerability arising from altered NAD+ homeostasis in CDKN2A-deleted glioblastoma, revealing a metabolic-genetic interface for rationally revisiting NAD+ targeting strategies, moving beyond the broad inhibition approaches.

Keywords:  CDKN2A; Glioblastoma; Glioma; NAD+; cell cycle

DOI:  https://doi.org/10.1093/noajnl/vdag088
Oncogene. 2026 Apr 20.

Thr3/Ser90 phosphorylation-stabilized S100A8 regulates cholesterol metabolism in glioblastoma stem cells.

Wanzhi Cai, Jingming Hu, Chengzhi Chen, Hao Shi, Lei Xu, Shenghao Zhu, Ning Liu, Xiuxing Wang, Jeremy N Rich, Yiming Tu, Jing Ji.

Glioblastoma (GBM) exhibits profound therapy resistance and inevitable recurrence, driven predominantly by glioblastoma stem cells (GSCs). S100A8 is positively associated with glioblastoma malignancy, but its expression and molecular mechanism in GSCs are poorly understood. Here, we demonstrated that S100A8 was highly expressed in GSCs and closely associated with shorter overall survival in GBM patients. The results showed that S100A8 maintained GSCs stemness by promoting cholesterol synthesis. Mechanistically, S100A8 bound to plasma membrane-localized RAGE, triggering ROS generation. Elevated ROS oxidized intracellular S100A8 at the Cys42 residue, thereby enhancing its affinity for mTORC1, subsequently inducing SREBP2-driven cholesterol synthesis. Furthermore, ROCK1-mediated phosphorylation of S100A8 at Thr3/Ser90, which stabilized S100A8 by impairing its binding to Fbxo10 and inhibiting the subsequent ubiquitination-mediated degradation. Our study reveals the S100A8-ROS-mTORC1 axis as a cholesterol metabolic vulnerability in GSCs, providing new insights into cholesterol metabolism and highlighting novel metabolism therapeutic strategies in GBM.

DOI: https://doi.org/10.1038/s41388-026-03799-5
Neuro Oncol. 2026 Apr 21. pii: noag085. [Epub ahead of print]

Modeling Gliomas with Organoids: Classification, Fidelity, and Guidelines for Translational Neuro-Oncology.

Christopher G Hubert, Renee D Read, Tyler E Miller, Uijin Kim, Xin Wang, Mohamed Ishan, Zhikun Wang, Emily Z Y Miller, Yusha Sun, Albert Lai, Guo-Li Ming, Hongjun Song, Zhaohui Wang.

  Advances in organoid technology have transformed how gliomas are modeled and studied. Recent FDA and NIH initiatives further promote human-relevant organoid platforms for preclinical research. Glioma organoids can be broadly categorized into three main classes: Engineered organoids, which enable controlled modeling of gliomagenesis driven by specific mutations; patient-tissue derived organoids, which preserve key molecular and histopathological features of the original tumors; and assembloids, which are designed to model tumor-microenvironment interactions. Together, these systems provide a human cell-relevant framework for investigating glioma biology, tumor-microenvironment crosstalk, and therapeutic responses and resistance. In this review, we provide a comprehensive overview of the spectrum of glioma organoid models, recognizing that different systems offer distinct and complementary strengths, and offer practical guidance for selecting appropriate models and analytical readouts based on specific basic and translational research objectives. To address increasing methodological heterogeneity and fragmented terminology, we propose a foundational nomenclature framework for glioma organoid models to improve clarity and communication within the field. We highlight applications in technically challenging subtypes, including isocitrate dehydrogenase (IDH)-mutant gliomas and diffuse midline gliomas (DMGs), and discuss key challenges-including scalability, standardization, microenvironment fidelity, and vascularization-and emerging innovations addressing these limitations. Finally, we call for greater collaboration and standardization within the glioma organoid community to accelerate the integration of organoid models into translational pipelines to redefine and refine preclinical modeling in neuro-oncology.

Keywords:  Glioma organoids; Preclinical models; Standardization and nomenclature; Translational neuro-oncology; Tumor microenvironment

DOI:  https://doi.org/10.1093/neuonc/noag085
Oncogene. 2026 Apr 21.

Targeting YRDC blocks codon-biased FABP7 translation and lipid droplet formation to overcome chemoresistance in glioblastoma.

Yuchao Zhang, Xuesong Yang, Xixi Li, Chen Zheng, Xuechao Zeng, Junju Chen, Mingpu Gao, Long Cheng, Zhenyan Xu, Lanjie Chen, Yixin Gao, Jian Zhong, Nunu Huang, Xuesong Liu, Kejun He, Nu Zhang, Xujia Wu.

Dysregulation of transfer RNA (tRNA) modification and reprogramming of codon-biased translation are commonly associated with cancer initiation and progression. However, their roles in chemoresistance and tumor recurrence remain poorly understood, especially in glioblastoma (GBM). This study establishes the tRNA-modifying enzyme YrdC N6-Threonylcarbamoyltransferase Domain Containing (YRDC) as a key mediator of temozolomide (TMZ) resistance in GBM. YRDC catalyzes the formation of N6-threonylcarbamoyladenosine (t6A) on ANN-decoding tRNAs (A denotes adenosine, and N denotes any nucleotide). YRDC expression is elevated in TMZ-resistant models and recurrent GBM, correlating with poor patient prognosis. Mechanistically, YRDC drives ANN codon-biased translation of target mRNAs, most notably encoding the fatty acid-binding protein FABP7. Elevated FABP7 induces lipid droplet accumulation, which sequesters TMZ-induced reactive oxygen species to mitigate oxidative stress and confer chemoresistance. Targeting this axis, we developed HY-Q66655, a novel blood-brain-barrier-penetrant YRDC inhibitor identified via virtual screening. HY-Q66655 directly inhibits YRDC, suppresses FABP7 translation, depletes lipid droplets, and acts synergistically with TMZ to inhibit tumor growth in vitro and in patient-derived orthotopic xenografts. The YRDC/FABP7 pathway is clinically associated with GBM recurrence, and HY-Q66655 demonstrates broad-spectrum anti-tumor activity across malignancies, revealing a tRNA modification-dependent mechanism and a potential therapeutic strategy.

DOI: https://doi.org/10.1038/s41388-026-03801-0
Neuro Oncol. 2026 Apr 21. pii: noag087. [Epub ahead of print]

NEU1 Sustains Mitochondria-Lysosome Contacts to Trigger Lysosomal Cu²⁺/Cathepsin Escape and Mitochondrial lysis in Glioblastoma (NeuLysis).

Yanping Huang, Dongyuan Su, Xiaoteng Cui, Yaqing Ding, Qi Zhan, Biao Hong, Jixing Zhao, Hanyi Xu, Longtao Cui, Chunchao Cheng, Jiasheng Ju, Qixue Wang, Yunfei Wang, Eryan Yang, Kaikai Yi, Dazhao Peng, Huimin Hu, Chunsheng Kang.

   BACKGROUND: Mitochondria-lysosome contacts regulates metabolic reprogramming in cancer, yet its role in glioblastoma pathogenesis remains poorly defined.
METHODS: We employed an integrated approach, including transmission electron microscopy (TEM) and Hessian-structured illumination microscopy (Hessian SIM), Fluorescence Resonance Energy Transfer-Fluorescence Lifetime Imaging (FRET-FLIM) assays, targeted metabolomics, mitochondrial respiration analyses, subcellular fractionation, and in vivo orthotopic xenograft models.
RESULTS: Genetic depletion or pharmacological disruption using EPIC-1042 against PTRF led to NEU1 destabilization via lysosome-dependent degradation, potentiating lysosomal function and prolonging mitochondria-lysosome contacts duration. Within this sustained contact state, dual flux transported from lysosomes to mitochondria: (1) Cu²⁺, which triggered DLAT aggregation and induced cuproptosis; and (2) cathepsin B, which caused mitochondrial protein degradation. Consequently, morphology and function were destroyed. NEU1 deficiency phenocopied these effects and heightened sensitivity to copper ionophore Elesclomol. Pharmacological inhibition of NEU1 with Oseltamivir synergized potently with Elesclomol to suppress intracranial glioblastoma overall growth and significantly extend survival in vivo.
CONCLUSIONS: We depict NeuLysis (NEU1-induced Lysosomal Escape leading to mitochondrial Lysis) as a novel cell death pathway in glioblastoma, wherein PTRF-NEU1 axis prolonged mitochondria-lysosome contacts. Pharmacological NEU1 inhibition with Oseltamivir synergizes Elesclomol-induced cell death, providing a preclinically actionable therapeutic strategy against glioblastoma.

Keywords:  Elesclomol; Glioblastoma; Mitochondria-lysosome contacts; Neuraminidase-1; Oseltamivir

DOI:  https://doi.org/10.1093/neuonc/noag087
Neuro Oncol. 2026 Apr 20. pii: noag088. [Epub ahead of print]

Prospective biopsy-controlled validation of an AI model for predicting glioblastoma infiltration: Results from the SupraGlio trial.

Santiago Cepeda, Elena Hernando-Pérez, Enrique Pérez-Riesgo, Isabel Rodríguez-Valle, Olga Esteban-Sinovas, Ignacio Arrese, María Miguel Lucero-Salaverry, Tomás Zamora, María Ángeles Torres-Nieto, Luigi Tommaso Luppino, Samuel Kuttner, Marek Wodzinski, Trinidad Escudero, Jesús Garzón, Roberto Romero-Oraá, Roberto Hornero, Lucía Núñez, Carlos Villalobos, Rosario Sarabia.

   BACKGROUND: Glioblastoma recurrence is driven by diffuse microscopic infiltration beyond the contrast-enhancing tumour margin. GlioMap is an open-access AI model predicting voxelwise infiltration and recurrence risk from multiparametric MRI. This prospective study aimed to validate GlioMap's biological accuracy and prognostic relevance through histopathological assessment, transcriptomic profiling, and survival analysis within the SupraGlio trial (NCT05735171).
METHODS: Patients with newly diagnosed glioblastoma underwent neuronavigated biopsies targeting AI-predicted high-risk (HRoR) and low-risk of recurrence (LRoR) regions beyond the contrast-enhancing tumour. Histopathological infiltration served as the ground truth, and transcriptomic profiling characterised each region's molecular phenotype. Model performance was evaluated using accuracy and area under the receiver operating characteristic (ROC) curve (AUC). Survival analyses assessed the prognostic value of postoperative HRoR volume.
RESULTS: Fifty-eight biopsies from 27 patients were analysed. GlioMap achieved 0.81 accuracy (95% CI, 0.71-0.91) and 0.84 AUC (95% CI, 0.73-0.93) for histologically confirmed infiltration. Transcriptomic analysis of 48 samples from 16 patients revealed progressive upregulation of invasion- and angiogenesis-related genes (CD44, CHI3L1, STAT3, VEGFA) and downregulation of neuronal markers (MBP, GABRA1) from LRoR to HRoR regions and tumour core, confirming a neural-to-mesenchymal gradient. Postoperative HRoR volume >1.6 cm³ predicted shorter overall survival (P = .04) and progression-free survival (P = .008).
CONCLUSIONS: To our knowledge, this study provides the first prospective, biopsy-controlled, molecular validation of an AI model for mapping glioblastoma infiltration. By accurately identifying histologically and transcriptionally infiltrated regions, GlioMap offers a biologically grounded imaging biomarker that could guide extended resection and personalised radiotherapy planning, potentially improving tumour control and patient outcomes.

Keywords:  artificial intelligence; glioblastoma; infiltration; radiomics; recurrence

DOI:  https://doi.org/10.1093/neuonc/noag088
Nat Immunol. 2026 Apr 23.

Astrocyte-driven immunosuppression in the brain tumor microenvironment.

Camilo Faust Akl, Francisco J Quintana.

Brain tumors are among the most lethal cancers, with limited success from emerging immunotherapies, largely due to the reshaping of the surrounding tumor microenvironment to promote tumor growth, invasion and immune evasion. Astrocytes are abundant glial cells of the central nervous system (CNS) that can activate distinct molecular programs to support glioblastoma and brain metastases. Although astrocytes are central regulators of the immune response in the CNS, their role in shaping tumor immunity remains relatively underexplored. Emerging evidence indicates that reactive astrocytes are important drivers of local immunosuppression, which constitutes a major barrier to the development of efficacious immunotherapies for brain tumors. In this Review, we examine astrocyte reprogramming by tumor-derived signals, its effect on tumor immunity, and emerging strategies to modulate astrocyte responses and immunotherapy outcomes.

DOI: https://doi.org/10.1038/s41590-026-02488-5