bims-malgli Biomed News
on Biology of malignant gliomas
Issue of 2025–01–26
nine papers selected by
Oltea Sampetrean, Keio University
  1. The clinical and molecular landscape of diffuse hemispheric glioma, H3 G34-mutant.
  2. Pre-Radiation Targeted Therapy for Highly Selected Patients with Newly Diagnosed Glioblastoma: New Tricks for an Old Dog?
  3. TGFBR2 High mesenchymal glioma stem cells phenocopy regulatory T cells to suppress CD4+ and CD8+ T cell function.
  4. Like, share, and spike: Glioblastoma progenitors influence neuronal excitability at the glioma-neural interface.
  5. Glioblastoma-derived migrasomes promote migration and invasion by releasing PAK4 and LAMA4.
  6. Impact of glioma metabolism-related gene ALPK1 on tumor immune heterogeneity and the regulation of the TGF-β pathway.
  7. VTE incidence shortens survival in IDH-WT glioblastoma.
  8. Targeting ARPC1B Overcomes Immune Checkpoint Inhibitor Resistance in Glioblastoma by Reversing Pro-tumorigenic Macrophage Polarization.
  9. Multidimensional, integrative profiling identifies BCL2L1 methylation as a predictor of MCL1 dependency in pediatric malignancies.
  1. Neuro Oncol. 2025 Jan 22. pii: noaf015. [Epub ahead of print]
    The clinical and molecular landscape of diffuse hemispheric glioma, H3 G34-mutant.
    H3 G34 DHG Study Group
       BACKGROUND: Diffuse hemispheric glioma, histone 3 (H3) G34-mutant, has been newly defined in the 2021 WHO classification of central nervous system tumors. Here we sought to define the prognostic roles of clinical, neuroimaging, pathological, and molecular features of these tumors.
    METHODS: We retrospectively assembled a cohort of 114 patients (median age 22 years) with diffuse hemispheric glioma, H3 G34-mutant, CNS WHO grade 4 and profiled the imaging, histological and molecular landscape of their tumors.
    RESULTS: Compared with glioblastoma, H3 G34-mutant diffuse hemispheric gliomas exhibited less avid contrast enhancement, necrosis and edema on MRI. Comprehensive analyses of mutational and DNA copy number profiles revealed recurrent mutations in TP53 and ATRX, homozygous deletions of CDKN2A/B, and amplifications of PDGFRA, EGFR, CCND2, and MYCN. MGMT promoter methylation was detected in 79 tumors (75%); 11 tumors (13%) showed DNA copy number profiles suggestive of circumscribed deletions on 10q26.3 involving the MGMT locus. Median survival was 21.5 months. Female sex, gross total resection, and MGMT promoter methylation were positive prognostic factors on univariate analysis. Among radiological, pathological and molecular features, absence of pial invasion, and presence of microvascular proliferation and CDK6 amplification were positive prognostic factors on univariate analyses.
    CONCLUSIONS: This study refines the clinical and molecular landscape of H3 G34-mutant diffuse hemispheric gliomas. Dedicated trials for this novel tumor type are urgently needed.
    Keywords:   MGMT ; Glioblastoma; histone; loss; methylation
    DOI:  https://doi.org/10.1093/neuonc/noaf015
  2. Neuro Oncol. 2025 Jan 24. pii: noaf014. [Epub ahead of print]
    Pre-Radiation Targeted Therapy for Highly Selected Patients with Newly Diagnosed Glioblastoma: New Tricks for an Old Dog?
    Macarena I de la Fuente, Andrew B Lassman.
      
    DOI:  https://doi.org/10.1093/neuonc/noaf014
  3. bioRxiv. 2025 Jan 08. pii: 2025.01.07.631757. [Epub ahead of print]
    TGFBR2 High mesenchymal glioma stem cells phenocopy regulatory T cells to suppress CD4+ and CD8+ T cell function.
    Amanda L Johnson, Harmon S Khela, Jack Korleski, Sophie Sall, Yunqing Li, Weiqiang Zhou, Karen Smith-Connor, Hernando Lopez-Bertoni, John Laterra.
      Attempts to activate an anti-tumor immune response in glioblastoma (GBM) have been met with many challenges due to its inherently immunosuppressive tumor microenvironment. The degree and mechanisms by which molecularly and phenotypically diverse tumor-propagating glioma stem cells (GSCs) contribute to this state are poorly defined. In this study, our multifaceted approach combining bioinformatics analyses of clinical and experimental datasets, single-cell sequencing, and molecular and pharmacologic manipulation of patient-derived cells identified GSCs expressing immunosuppressive effectors mimicking regulatory T cells (Tregs). We show that this I mmunosuppressive T reg- L ike (ITL) GSC state is specific to the mesenchymal GSC subset and is associated with and driven specifically by TGF-β type II receptor (TGFBR2) in contrast to TGFBR1. Transgenic TGFBR2 expression in patient-derived GBM neurospheres promoted a mesenchymal transition and induced a 6-gene ITL signature consisting of CD274 (PD-L1), NT5E (CD73), ENTPD1 (CD39), LGALS1 (galectin-1), PDCD1LG2 (PD-L2), and TGFB1. This TGFBR2-driven ITL signature was identified in clinical GBM specimens, patient-derived GSCs and systemic mesenchymal malignancies. TGFBR2 High GSCs inhibited CD4+ and CD8+ T cell viability and their capacity to kill GBM cells, effects reversed by pharmacologic and shRNA-based TGFBR2 inhibition. Collectively, our data identify an immunosuppressive GSC state that is TGFBR2-dependent and susceptible to TGFBR2-targeted therapeutics.
    DOI:  https://doi.org/10.1101/2025.01.07.631757
  4. Neuron. 2025 Jan 22. pii: S0896-6273(24)00920-6. [Epub ahead of print]113(2): 185-186
    Like, share, and spike: Glioblastoma progenitors influence neuronal excitability at the glioma-neural interface.
    Christopher W Mount, Mario L Suvà.
      Writing in Neuron, Zhang et al. identify a subpopulation of glioblastoma cells from patient tumor samples with progenitor-like features that expresses the potassium ion channel KCND2.1 In mouse and organoid models, these cells enhance neural activity at the glioma-neural interface.
    DOI:  https://doi.org/10.1016/j.neuron.2024.12.021
  5. Commun Biol. 2025 Jan 20. 8(1): 91
    Glioblastoma-derived migrasomes promote migration and invasion by releasing PAK4 and LAMA4.
    Zhe Huang, Ming Wang, Yitian Chen, Hua Tang, Kuo Tang, Mingkuan Zhao, Wei Yang, Zhengjun Zhou, Junjie Tian, Wei Xiang, Shenjie Li, Qinglian Luo, Luotong Liu, Yanru Zhao, Tao Li, Jie Zhou, Ligang Chen.
      Almost all high-grade gliomas, particularly glioblastoma (GBM), are highly migratory and aggressive. Migrasomes are organelles produced by highly migratory cells capable of mediating intercellular communication. Thus, GBM cells may produce migrasomes during migration. However, it remains unclear whether migrasomes can influence GBM migration and invasion. In this study, we observed the presence and formation of migrasomes in GBM cells. We found that expression levels of key migrasome formation factor, tetraspanin 4 (TSPAN4), correlated positively with pathological grade and poor prognosis of GBM based on the databases and clinical samples analysis. Subsequently, we knocked down TSPAN4 and found that GBM cell migration and invasion were significantly inhibited due to the reduced formation of migrasomes. We further confirmed that migrasomes are enriched in extracellular matrix (ECM)-related proteins such as p21-activating kinase 4 (PAK4) and laminin alpha 4 (LAMA4). Our experimental results suggest that migrasomes promote GBM cells migration by releasing such proteins into the extracellular space. Overall, we identified migrasomes in GBM and the molecular mechanisms by which they regulate them, providing potential targets for treating GBM.
    DOI:  https://doi.org/10.1038/s42003-025-07526-w
  6. Front Immunol. 2024 ;15 1512491
    Impact of glioma metabolism-related gene ALPK1 on tumor immune heterogeneity and the regulation of the TGF-β pathway.
    YaoFeng Hu, Sen Qin, RuCui Deng.
       Background: Recent years have seen persistently poor prognoses for glioma patients. Therefore, exploring the molecular subtyping of gliomas, identifying novel prognostic biomarkers, and understanding the characteristics of their immune microenvironments are crucial for improving treatment strategies and patient outcomes.
    Methods: We integrated glioma datasets from multiple sources, employing Non-negative Matrix Factorization (NMF) to cluster samples and filter for differentially expressed metabolic genes. Additionally, we utilized Weighted Gene Co-expression Network Analysis (WGCNA) to identify key genes. A predictive model was developed utilizing the optimal consistency index derived from a combination of 101 machine learning techniques, and its effectiveness was confirmed through multiple datasets employing different methodologies. In-depth analyses were conducted on immune cell infiltration and tumor microenvironmental aspects. Single-cell sequencing data were employed for clustering and differential expression analysis of genes associated with glioma. Finally, the immune relevance of the model gene ALPK1 in the context of pan-cancer was explored, including its relationship with immune checkpoints.
    Results: The application of NMF, coupled with differential analysis of metabolic-related genes, led to the identification of two clusters exhibiting significant differences in survival, age, and metabolic gene expression among patients. Core genes were identified through WGCNA, and a total of 101 machine learning models were constructed, with LASSO+GBM selected as the optimal model, demonstrating robust validation performance. Comprehensive analyses revealed that high-risk groups exhibited greater expression of specific genes, with ALPK1 showing significant correlations with immune regulation.
    Conclusion: This research employed a multi-dataset strategy and various methods to clarify the differences in metabolic traits and immune conditions in glioma patients, while creating an innovative prognostic risk evaluation framework. These results offer fresh perspectives on the intricate biological processes that define gliomas.
    Keywords:  ALPK1; glioma; immune microenvironment; metabolic genes; prognostic biomarkers
    DOI:  https://doi.org/10.3389/fimmu.2024.1512491
  7. medRxiv. 2025 Jan 09. pii: 2025.01.08.25319908. [Epub ahead of print]
    VTE incidence shortens survival in IDH-WT glioblastoma.
    Anthony R Sloan, Alan J Gordillo, Austin Kennemer, Alok A Khorana, Craig Horbinski, David C Kaelber, Scott J Cameron, Justin D Lathia.
       Background: Venous thromboembolisms (VTE's) are the second leading cause of death in cancer patients. While previous analyses have demonstrated VTE rates are greater in GBM patients using smaller patient cohorts in high-grade glioma, since the release of the update 5 th edition of the World Health Organization (WHO) classification a systematic analysis in a large-scale cohort of patients with IDH-wildtype GBM with clinical outcomes is lacking.
    Methods: This study utilizes the online database, TriNetx, to build patient cohorts for outcomes analysis. TriNetX is a database comprised of over 50 healthcare organization patient information that is quarriable by CPT, ICD, RxNorm, and other proprietary codes. Patient cohort demographics were used for propensity score matching. Risk ratios, odds ratios, hazard ratios, and Kaplan Meier curves were utilized for primary outcomes including survival and time-to-event analyses.
    Results: 24% of patients with GBM experienced at least 1 VTE or PE after their diagnosis. Compared to a population of patients with no cancer history with an index event of an inpatient visit, patients with GBM were at 20.4 (12.23-34.17) and 5.96 (3.85-9.23) times higher risk of experiencing a VTE/PE at 1- and 5-year follow-up, respectively. Sex differences were not seen between VTE/PE rates and survival after VTE/PE at 1- and 5-year follow-up (p>0.05). Lastly, patients with GBM and a VTE/PE after diagnosis experienced worse survival at 1- and 5-year follow-up compared to those without a VTE/PE (p<0.0001 and p = 0.0014, respectively).
    Conclusions: Patients with GBM experience increased risks of thrombotic events after diagnosis. These risks are not sex-dependent but do affect overall survival.
    DOI:  https://doi.org/10.1101/2025.01.08.25319908
  8. Cancer Res. 2025 Jan 22.
    Targeting ARPC1B Overcomes Immune Checkpoint Inhibitor Resistance in Glioblastoma by Reversing Pro-tumorigenic Macrophage Polarization.
    Tianqi Liu, Tao Sun, Xin Chen, Jianqi Wu, Xiaoqian Sun, Xing Liu, Haixu Yan, Qiang Fu, Zirong Fan, Xiangyu Wang, Peng Cheng, Wen Cheng, Anhua Wu.
      Immunotherapy has elicited significant improvements in outcomes for patients with several tumor types. However, the immunosuppressive microenvironment in glioblastoma restricts the therapeutic efficacy of immune checkpoint blockade (ICB). In this study, we investigated which components of the immune microenvironment contribute to ICB failure in glioblastoma to elucidate the underlying causes of immunotherapeutic resistance. Macrophages were identified as a main contributor to ICB resistance. Expression of ARPC1B, a regulatory subunit of the Arp2/3 complex, was elevated in glioblastoma and correlated with macrophage enrichment and prognosis. ARPC1B in tumor cells increased STAT1 expression and subsequent IL10 production, which induced a pro-tumorigenic macrophage state. Mechanistically, ARPC1B inhibited the ubiquitination and degradation of STAT1 by preventing the E3 ubiquitin ligase NEDD4L from binding to STAT1 and by supporting the interaction between STAT1 and the deubiquitinase USP7. Inhibiting ARPC1B reshaped the immunosuppressive microenvironment and increased the efficacy of ICB in glioblastoma models. This study highlights the important role of ARPC1B in macrophage-mediated immunosuppression and proposes a combination treatment regimen for glioblastoma immunotherapy.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-24-2286
  9. JCI Insight. 2025 Jan 23. pii: e184601. [Epub ahead of print]10(2):
    Multidimensional, integrative profiling identifies BCL2L1 methylation as a predictor of MCL1 dependency in pediatric malignancies.
    Shazia Adjumain, Paul Daniel, Claire Xin Sun, Gabrielle Bradshaw, Nicole J Chew, Vanessa Tsui, Hanbyeol Lee, Melissa Loi, Nataliya Zhukova, Dilru Habarakada, Abigail Yoel, Vijesh G Vaghjiani, Shaye Game, Louise E Ludlow, Naama Neeman, E Alejandro Sweet-Cordero, David D Eisenstat, Jason E Cain, Ron Firestein.
      Pediatric high-grade gliomas (pHGGs) are the most aggressive brain tumors in children, necessitating innovative therapies to improve outcomes. Unlike adult gliomas, recent research reveals that childhood gliomas have distinct biological features, requiring specific treatment strategies. Here, we focused on deciphering unique genetic dependencies specific to childhood gliomas. Using a pooled CRISPR/Cas9 knockout screening approach on 65 pediatric and 10 adult high-grade glioma (HGG) cell lines, myeloid cell leukemia 1 (MCL1) emerged as a key antiapoptotic gene essential in pediatric but not adult gliomas. We demonstrated that MCL1 is targetable using current small molecule inhibitors, and its inhibition leads to potent anticancer activity across pediatric HGG cell lines irrespective of genotype. Employing predictive modeling approaches on a large set of childhood cancer cell lines with multiomics data features, we identified a potentially previously unreported cluster of CpG sites in the antiapoptotic BCL-xL/BCL2L1 gene, which predicted MCL1 inhibitor response. We extended these data across multiple pediatric tumor types, showing that BCL2L1 methylation is a broad predictor of MCL1 dependency in vitro and in vivo. Overall, our multidimensional, integrated genomic approach identified MCL1 as a promising therapeutic target in several BCL2L1-methylated pediatric cancers, offering a translational strategy to identify patients most likely to benefit from MCL1 inhibitor therapy.
    Keywords:  Clinical trials; Drug therapy; Therapeutics
    DOI:  https://doi.org/10.1172/jci.insight.184601
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