bims-malgli 2025-08-03 papers

bims-malgli

Biomed News

on Biology of malignant gliomas

Issue of 2025–08–03
seven papers selected by
Oltea Sampetrean, Keio University

Mitochondrial Calcium Uniporter Links Acetyl-CoA Metabolism and H3K27 Acetylation to Maintain Glioblastoma Stem Cells.
Mitochondrial inflexibility ignites tumor immunogenicity in postoperative glioblastoma.
Intra-tumoral Preservation of the Stem-like Malignant Cell Proportion in Glioblastoma, Prognostic Impact, and its Radiomethylomic Signatures.
Update to the RANO working group and EANO recommendations for the clinical use of PET imaging in gliomas.
Glioma-Associated Microglia Potentiate Neuronal Hyper-Excitability in the Glioma Environment.
A diverse landscape of FGFR alterations and co-mutations suggests potential therapeutic strategies in pediatric low-grade gliomas.
Long-term survival and cure fraction estimates for paediatric central nervous system tumours in 31 European countries (EUROCARE-6): a population-based study.

Cancer Res. 2025 Jul 25.

Mitochondrial Calcium Uniporter Links Acetyl-CoA Metabolism and H3K27 Acetylation to Maintain Glioblastoma Stem Cells.

Guangqin Liu, Haoqian Zhang, Siqi Chen, Jun Gao, Haixin Zhao, Yan Dong, Changwei Liu, Xuechen Wei, Ting Li, Chang Lu, Haizhen Zhu, Dingyi Lu, Shiyu Feng, Teng Li, Weina Zhang, Qing Xia, Jianghong Man, Tao Zhou, Jiayi Chen, Ailing Li, Xin Pan.

Glioblastoma stem cells (GSCs) exhibit remarkable metabolic and epigenetic adaptability, contributing to therapeutic resistance and tumor recurrence. The mechanisms underlying this plasticity represent potential targetable vulnerabilities to improve glioblastoma treatment. Here, we identified a critical metabolic-epigenetic axis centered on the mitochondrial calcium uniporter (MCU) that governs GSC survival and tumor initiation. MCU was preferentially expressed in GSCs, and loss of MCU significantly impaired GSC self-renewal and viability. Mechanistically, MCU enhanced mitochondrial calcium uptake, promoting acetyl-CoA production via pyruvate dehydrogenase activation. Elevated acetyl-CoA levels drove histone H3K27 acetylation at the TRIB3 locus to maintain GSC growth. In glioblastoma patients, higher MCU expression was correlated with increased acetyl-CoA levels, elevated H3K27 acetylation, enhanced TRIB3 expression, higher tumor grade, and poorer survival. Pharmacological inhibition of MCU with berberine suppressed GSC growth and extended survival in mouse GBM models. These findings establish MCU as a critical link between mitochondrial metabolism and epigenetic regulation, highlighting its potential as a therapeutic target for glioblastoma.

DOI: https://doi.org/10.1158/0008-5472.CAN-25-0419
Nat Commun. 2025 Jul 28. 16(1): 6946

Mitochondrial inflexibility ignites tumor immunogenicity in postoperative glioblastoma.

Lulu Cheng, Zezheng Fang, Junpeng Wang, Kaiyan Xi, Yi Zhang, Fan Feng, Le Yu, Myla Santiago, Jingjing Wang, Zimei Wu, Kang-Nan Wang, Thomas Daubon, Shilei Ni, Yanrong Zhang, Yulin Zhang.

Cellular and molecular heterogeneity contributes to the insufficient immunogenicity of glioblastoma multiforme (GBM), a lethal malignancy characterized by post-resection relapse, ultimately leading to limited immune cell infiltration. Here, we report a strategy to boost tumor immunity by activating the endogenous cGAS-STING signaling pathway through in-situ manipulation of the mitochondrial electron transport chain (ETC), thereby augmenting the immune responsiveness of GBM. Under white light irradiation, the synthetic butterfly-shaped photosensitizer B-TTPy disrupts the mitochondrial ETC by producing excessive reactive oxygen species. Synergistically, inhibition of checkpoint kinase 1 amplifies ETC dysfunction, thus enhancing the cytotoxicity of B-TTPy against tumor cells. Our results demonstrate that the in-house-customized Mitochondrial Electron Alteration Nanoparticles in Glioblastoma (MEANING) efficiently activate innate and adaptive immune response by recruiting antigen-presenting cells and cytotoxic T cells to the surgical margin. Moreover, biodegradable hydrogel-medicated surgical cavity treatment with MEANING can reshape the immunosuppressive tumor microenvironment and eliminate residual GBM cells. In sum, our findings establish a local immune activation approach for GBM, to prevent postoperative tumor recurrence and identify ETC blockade as a promising therapeutic strategy for low-immunogenic tumors.

DOI: https://doi.org/10.1038/s41467-025-62244-5
Neuro Oncol. 2025 Jul 28. pii: noaf175. [Epub ahead of print]

Intra-tumoral Preservation of the Stem-like Malignant Cell Proportion in Glioblastoma, Prognostic Impact, and its Radiomethylomic Signatures.

Yuji Matsumoto, Omkar Singh, Jose Garcia, Zied Abdullaev, Nelson F Freeburg, Fanyang Yu, Hamed Akbari, Kyunglok Baik, Jun Guo, Natalie N C Shih, Erik Toorens, Tapan Ganguly, Dominique Ballinger, Donald M O'Rourke, Suyash Mohan, Jennifer J D Morrissette, Dana Silverbush, Kenneth Aldape, Christos Davatzikos, MacLean P Nasrallah.

   BACKGROUND: Glioblastoma (GBM) exhibits significant intra-tumoral heterogeneity. However, the presence and extent of intra-tumoral heterogeneity of stem-like and differentiated cell components based on methylation profiles remain poorly understood. Furthermore, the utility of integrating methylation profiles with radiomic features (radiomethylomics) for predicting these cellular states has not been explored.
METHODS: We analyzed 248 samples from 133 GBM patients, including 157 samples from 42 patients whose tumors were sampled at multiple points. Two distinct methylation-based deconvolution analyses were performed to assess cellular composition. Radiomethylomic models were developed using support vector machines with features extracted from multiparametric MRI.
RESULTS: Multi-sampling analysis revealed that the proportion of stem-like cells among total malignant cells was homogeneously preserved within tumors. Tumors harboring a higher proportion of stem-like cells (Stem-like Tumors) showed significantly shorter overall survival and diminished benefits from O6-methylguanine DNA methyltransferase (MGMT) promoter methylation. Stem-like Tumors showed a strong correlation with the RTK I subtype. Integrating physiological MRI features (DTI and DSC) with conventional sequences enhanced the performance of radiomethylomic models for predicting Stem-like Tumor status and prognostic stratification.
CONCLUSIONS: Our findings reveal a homogeneous preservation of the proportion of stem-like cells over total malignant cells within GBM, establishing its significance as a tumor-wide feature. The development of radiomethylomic signatures shows potential for non-invasive assessment of tumor stemness, ultimately facilitating personalized treatment strategies in light of the prognostic impact of the feature.

Keywords:  DNA methylation; glioblastoma; heterogeneity; radiomics; stem-like cells

DOI:  https://doi.org/10.1093/neuonc/noaf175
Lancet Oncol. 2025 Aug;pii: S1470-2045(25)00193-7. [Epub ahead of print]26(8): e436-e447

Update to the RANO working group and EANO recommendations for the clinical use of PET imaging in gliomas.

Norbert Galldiks, Philipp Lohmann, Mariam Aboian, Ramon F Barajas, William G Breen, Jana Ivanidze, Derek R Johnson, Timothy J Kaufmann, Michelle M Kim, Maximilian J Mair, Giuseppe Minniti, Michael Müther, Ali Nabavizadeh, Joshua D Palmer, Roberta Rudà, Marion Smits, Nelleke Tolboom, Sophie E M Veldhuijzen van Zanten, Michael C Veronesi, Jan-Michael Werner, Martin van den Bent, Susan M Chang, Karl-Josef Langen, Ian Law, Jonathan McConathy, Minesh Mehta, Matthias Preusser, Susan C Short, Riccardo Soffietti, Michael Vogelbaum, Michael Weller, Patrick Y Wen, Joerg-Christian Tonn, Nathalie L Albert.

This Policy Review provides recommendations for the use of PET imaging in patients with gliomas and represents a joint effort of the Response Assessment in Neuro-Oncology (RANO) working group for PET and the European Association for Neuro-Oncology. The initial guideline was published in 2016, and summarised the previously established clinical benefit of PET with radiolabelled glucose and amino acid tracers in patients with gliomas. Since then, numerous additional studies have been published on this topic, focusing on differential diagnosis, prediction of molecular information, and prognostication. Further studies evaluated PET for biopsy guidance and delineation of glioma extent for local therapy planning, including resection and radiotherapy. In patients undergoing treatment, PET was studied for the assessment of response to local and systemic treatments and PET-based standardised response criteria (PET RANO 1.0) were proposed. In this Policy Review, the updated recommendations are based on evidence generated from studies that validated PET findings by histomolecular findings or clinical course. This guideline further underscores the previously reported clinical value of PET imaging and the superiority of amino acid PET over glucose PET, providing a framework for the use of PET in the management of patients with gliomas. The guideline also underscores the scarcity of class 1 evidence showing that incorporating PET imaging into clinical workflows improves patient outcomes, highlighting priority areas for future clinical studies designed to address this gap.

DOI: https://doi.org/10.1016/S1470-2045(25)00193-7
Neuro Oncol. 2025 Jul 30. pii: noaf181. [Epub ahead of print]

Glioma-Associated Microglia Potentiate Neuronal Hyper-Excitability in the Glioma Environment.

Jaeseung Yei, Na Kyeong Lee, Seungmin Ryu, Seong-Eun Ryu, Juheon Lee, Taeyoung Park, Yoonyi Jeong, Rian Kang, Ho-Keun Kwon, Seong-Gi Kim, Jong-Chan Park, Chun Gwon Park, Minah Suh.

   BACKGROUND: Hyper-excitable neurons are observed in the glioma brain, contributing to the notorious nature of glioma. It is well established that microglia can modulate neuronal excitability through crosstalk via P2RY12. However, the role of microglia in glioma environments remains poorly understood. Thus, this study aimed to investigate whether loss of microglial P2RY12 could contribute to hyper-excitable neurons within the glioma environment.
METHODS: Using two distinct tumor models and normal Thy1-GCaMP6f mice, spontaneous neuronal activity was imaged in the peritumor region with an in vivo 2-photon microscope. Neuronal calcium activity was then compared to expression level of microglial P2RY12. Neuronal activity was further quantified after administering a microglial blocker and compared across different tumor models and cortical regions of a glioma mouse model.
RESULTS: Our findings revealed that hyper-excitable neurons were exclusively observed in cortical regions surrounding glioma tissues. In the glioma environment, microglia exhibited significantly reduced expression of P2RY12, a receptor known to modulate neuronal activity via negative feedback control. In contrast, neuronal excitability and microglial P2RY12 expression relatively remained same to the control in environments of a brain metastasis model. Furthermore, blocking microglial P2RY12 enhanced spontaneous neuronal activity in both the brain metastasis model and distal regions of glioma tumors, effectively replicating the functional loss of P2RY12 observed in glioma conditions.
CONCLUSIONS: Results of this study support that neuronal hyper-excitability is a unique observation within a peri-glioma environment driven by loss of microglial P2RY12.

Keywords:  Glioma; Microglia; Neuronal hyper-excitability; P2RY12

DOI:  https://doi.org/10.1093/neuonc/noaf181
Nat Commun. 2025 Jul 31. 16(1): 7018

A diverse landscape of FGFR alterations and co-mutations suggests potential therapeutic strategies in pediatric low-grade gliomas.

April A Apfelbaum, Eric Morin, Dominik Sturm, Georges Ayoub, Jeromy DiGiacomo, Sher Bahadur, Bhavyaa Chandarana, Phoebe C Power, Margaret M Cusick, Dana Novikov, Prem Prabhakar, Robert E Jones, Jayne Vogelzang, Connor C Bossi, Seth Malinowski, Lewis M Woodward, Tania A Jones, John Jeang, Sarah W Lamson, Jared Collins, Kelly Y Cai, Jacquelyn S Jones, Sehee Oh, Hyesung Jeon, Jinhua Wang, Amy Cameron, Patrick Rechter, Angela De Leon, Karthikeyan Murugesan, Meagan Montesion, Lee A Albacker, Shakti H Ramkissoon, Cornelis M van Tilburg, Emily C Hardin, Philipp Sievers, Felix Sahm, Kee Kiat Yeo, Tom Rosenberg, Susan N Chi, Karen D Wright, Steven Hébert, Sydney Peck, Alberto Picca, Valérie Larouche, Samuele Renzi, Sara J Buhrlage, Tejus A Bale, Amy A Smith, Mehdi Touat, Nada Jabado, Eric S Fischer, Michael J Eck, Lissa Baird, Olaf Witt, Claudia L Kleinman, Quang-De Nguyen, Denise Sheer, Sanda Alexandrescu, David T W Jones, Keith L Ligon, Pratiti Bandopadhayay.

Oncogenic alterations in fibroblast growth factor receptor (FGFR)-family proteins occur across cancers, including pediatric gliomas. Our genomic analysis of 11,635 gliomas across ages finds that 5.3% of all gliomas harbor FGFR alterations, with an incidence of almost 9% in pediatric gliomas. Alterations in FGFR proteins are differentially enriched by age, tumor grade, and histology, with FGFR1 alterations associated with glioneuronal histologies. Leveraging isogenic systems, we confirm FGFR1 alterations to induce downstream Mitogen Activated Protein Kinase (MAPK) and mTOR signaling pathways, drive gliomagenesis, activate neuronal transcriptional programs and exhibit sensitivity to MAPK pathway and pan-FGFR inhibitors. Finally, we perform a retrospective analysis of clinical responses in children diagnosed with FGFR-altered gliomas and find that treatment with currently available inhibitors is largely associated with stability of disease. This study provides key insights into the biology of FGFR1-altered gliomas, therapeutic strategies to target them and associated challenges that still need to be overcome.

DOI: https://doi.org/10.1038/s41467-025-61820-z
Lancet Oncol. 2025 Aug;pii: S1470-2045(25)00297-9. [Epub ahead of print]26(8): 1091-1099

Long-term survival and cure fraction estimates for paediatric central nervous system tumours in 31 European countries (EUROCARE-6): a population-based study.

EUROCARE working group

BACKGROUND: Clinically relevant survival outcomes, including cure fraction estimates, and long-term survival outcomes of paediatric CNS tumours from large-scale databases have not been reported for Europe. Moreover, various biases hinder direct geographical comparisons, thereby limiting the effective translation of population-based findings into cancer care, surveillance, and research. We aimed to estimate these survival outcomes across Europe through the EUROCARE database.
METHODS: In this population-based study, we analysed survival data from the EUROCARE-6 database from children younger than 15 years with a CNS tumour across 31 European countries. For the period 2008-13, we estimated observed survival via the actuarial method, and 5-year observed survival was reported at the European level and national level for four major CNS tumour groups. For the period 1998-2013, cure fraction was estimated through a mixture cure model assuming constant long-term mortality from other causes. Additionally, model-based 10-year and 15-year survival were estimated.
FINDINGS: For observed survival analyses, 13 782 tumour cases were included. 5-year observed survival was 72% (95% CI 68 to 75) for ependymomas, 92% (91 to 93) for low-grade gliomas, 47% (45 to 49) for high-grade gliomas, 24% (21 to 27) for high-grade gliomas excluding glioma not otherwise specified, and 64% (62 to 67) for medulloblastomas. A total of 30 392 children were included in the cure fraction analysis. During the study period, the largest absolute increase in cure fraction was observed for ependymomas from 65% (57 to 73) in 1998-2001 to 79% (69 to 89) in 2010-13, whereas low-grade gliomas increased from from 89% (85 to 94) to 95% (89 to 100), high-grade gliomas had a 6 percentage point change increase (2 to 10), and medulloblastomas increased from 52% (49 to 55) to 56% (51 to 60). The estimated 10-year and 15-year survival rates were highest for low-grade gliomas at 90·6% (89·4 to 91·7) at 10 years and 88·5% (87·2 to 89·8) at 15 years, whereas the lowest survival rates were observed for high-grade gliomas excluding glioma not otherwise specified at 20·5% (17·0 to 24·1) and 19·0% (15·6 to 22·5).
INTERPRETATION: This study is the first to report a comprehensive evaluation of survival parameters for paediatric CNS tumour patients in Europe. These outcomes are important to evaluate advances in care for children with a CNS tumour.
FUNDING: Princess Máxima Center for Pediatric Oncology and Associazione Italiana per la Ricerca sul Cancro.

DOI: https://doi.org/10.1016/S1470-2045(25)00297-9