bims-malgli Biomed News
on Biology of malignant gliomas
Issue of 2025–01–19
thirteen papers selected by
Oltea Sampetrean, Keio University
  1. Discontiguous recurrences of IDH-wildtype glioblastoma share a common origin with the initial tumor and are frequently hypermutated.
  2. A fetal oncogene NUAK2 is an emerging therapeutic target in glioblastoma.
  3. Hypoxia-induced circPLOD2a/b promotes the aggressiveness of glioblastoma by suppressing XIRP1 through binding to HuR.
  4. Phase I study of adavosertib with radiation therapy and temozolomide in newly diagnosed glioblastoma and intratumoral drug levels in recurrent glioblastoma.
  5. Distinct myeloid-derived suppressor cell populations in human glioblastoma.
  6. Human brain organoids identify glioma inhibitors.
  7. Personalising glioblastoma medicine: explant organoid applications, challenges and future perspectives.
  8. Amphiphilic hemicyanine molecular probes crossing the blood-brain barrier for intracranial optical imaging of glioblastoma.
  9. Tracing tumor-neuronal connectivity in glioblastoma.
  10. Disease stage-specific role of the mitochondrial pyruvate carrier suppresses differentiation in temozolomide and radiation-treated glioblastoma.
  11. Analysis of Circulating Plasma MicroRNA Profile in Low-Grade and High-Grade Glioma - A Cross-Sectional Study.
  12. Genetic predisposition to altered blood cell homeostasis is associated with glioma risk and survival.
  13. Brain-wide neuronal circuit connectome of human glioblastoma.
  1. Acta Neuropathol Commun. 2025 Jan 16. 13(1): 9
    Discontiguous recurrences of IDH-wildtype glioblastoma share a common origin with the initial tumor and are frequently hypermutated.
    Malcolm F McDonald, Sricharan Gopakumar, Tareq A Juratli, Ilker Y Eyüpoglu, Ganesh Rao, Jacob J Mandel, Ali Jalali.
      Glioblastoma is the deadliest primary brain tumor, largely due to inevitable recurrence of the disease after treatment. While most recurrences are local, patients rarely present with a new discontiguous focus of glioblastoma. Little is currently known about the genetic profile of discontiguous recurrences. In our institutional database, we identified 22 patients with targeted exome sequencing of pairs of initial and recurrent IDH-wildtype glioblastoma. Recurrences were classified as contiguous or discontiguous based on the presence or absence of T2 FLAIR signal connection to the initial site of disease on MRI. Exome analysis revealed shared driver and passenger mutations between discontiguous recurrences and initial tumors, supporting a common origin. Discontiguous recurrences were more likely to be hypermutated compared to contiguous recurrences (p = 0.038). Analysis of 2 glioblastoma cases with discontiguous recurrence at a collaborating institution also exhibited hypermutation. In conclusion, discontiguous glioblastoma recurrences share a common origin with the initial tumor and are more likely to be hypermutated than contiguous recurrences.
    Keywords:  Discontiguous; Glioblastoma recurrence; Hypermutation; IDH WT glioma; Multicentric
    DOI:  https://doi.org/10.1186/s40478-024-01900-1
  2. bioRxiv. 2025 Jan 02. pii: 2024.12.31.630965. [Epub ahead of print]
    A fetal oncogene NUAK2 is an emerging therapeutic target in glioblastoma.
    Hanhee Jo, Aneesh Dalvi, Wenqi Yang, Elizabeth Morozova, Sarah Munoz, Stacey M Glasgow.
      Glioblastoma Multiforme (GBM) is the most prevalent and highly malignant form of adult brain cancer characterized by poor overall survival rates. Effective therapeutic modalities remain limited, necessitating the search for novel treatments. Neurodevelopmental pathways have been implicated in glioma formation, with key neurodevelopmental regulators being re- expressed or co-opted during glioma tumorigenesis. Here we identified a serine/threonine kinase, NUAK family kinase 2 (NUAK2), as a fetal oncogene in mouse and human brains. We found robust expression of NUAK2 in the embryonic brain that decreases throughout postnatal stages and then is re-expressed in malignant gliomas. However, the role of NUAK2 in GBM tumorigenesis remains unclear. We demonstrate that CRIPSR-Cas9 mediated NUAK2 deletion in GBM cells results in suppression of proliferation, while overexpression leads to enhanced cell growth in both in vitro and in vivo models. Further investigation of the downstream biological processes dysregulated in the absence of NUAK2 reveals that NUAK2 modulates extracellular matrix (ECM) components to facilitate migratory behavior. Lastly, we determined that pharmaceutical inhibition of NUAK2 is sufficient to impede the proliferation and migration of malignant glioma cells. Our results suggest that NUAK2 is an actionable therapeutic target for GBM treatment.
    DOI:  https://doi.org/10.1101/2024.12.31.630965
  3. Commun Biol. 2025 Jan 17. 8(1): 71
    Hypoxia-induced circPLOD2a/b promotes the aggressiveness of glioblastoma by suppressing XIRP1 through binding to HuR.
    Aixin Yu, Yiqi Wang, Chao Duan, Jun Qin, Miaomiao Liao, Haiyan Zhu, Junrong Lei, Jun Liu, Zehao Yang, Li Yu, Hui Gui, Jinxin Xin, Weiwei Tao, Wendai Bao, Zhiqiang Dong.
      Hypoxia is a common feature of glioblastoma (GBM). Circular RNAs (circRNAs) are identified as regulators in cancers. However, the role of circRNAs in GBM remains elusive. Here, circPLOD2a and circPLOD2b, spliced from the same parental gene PLOD2, are identified as hypoxia-responsive circRNAs. Overexpression of circPLOD2a and b enhance while knockdown inhibit GBM cell aggressiveness. The protein partners and downstream molecules were investigated by RNA-pulldown, mass spectrometry and RNA-seq. Mechanistically, HIF1α induces the expression of circPLOD2a and b, which competitively bind to HuR, causing a degradation of XIRP1 in vitro and in vivo. Clinical data demonstrate circPLOD2a and b are highly expressed in GBM negatively correlated with XIRP1, whose lower expression associates with higher glioma grade and worse prognosis. In conclusion, hypoxia-induced circPLOD2a and b are oncogenic regulators of tumour aggressiveness through attenuating the interaction between HuR and XIRP1 in glioblastoma cells and may be potential therapeutic targets for this disease.
    DOI:  https://doi.org/10.1038/s42003-025-07503-3
  4. Clin Cancer Res. 2025 Jan 17.
    Phase I study of adavosertib with radiation therapy and temozolomide in newly diagnosed glioblastoma and intratumoral drug levels in recurrent glioblastoma.
    Eudocia Q Lee, Brian M Alexander, Carlos G Romo, Jeffrey G Supko, Nathalie Y R Agar, Zahra Talebi, Manmeet S Ahluwalia, Arati S Desai, Jorg Dietrich, Thomas J Kaley, David M Peereboom, Jennifer Gantchev, Gerard Baquer, Sandro Santagata, Naoko Takebe, Serena Desideri, Joy D Fisher, Megan Sims, Xiaobu Ye, Keith L Ligon, Louis B Nabors, Stuart A Grossman, Patrick Y Wen.
       PURPOSE: Adavosertib is an oral small molecular inhibitor of Wee1. The Adult Brain Tumor Consortium performed a phase I study of adavosertib, radiation (RT) and temozolomide (TMZ) in newly diagnosed glioblastoma (GBM) as well as a surgical window of opportunity study in recurrent GBM.
    PATIENTS AND METHODS: The maximum tolerated dose (MTD) of adavosertib was determined in adult patients with newly diagnosed GBM using a standard 3+3 design in 2 separate cohorts: with concurrent RT/TMZ or with adjuvant TMZ. A combination cohort with both concurrent and adjuvant adavosertib at MTD followed. We also performed intratumoral drug distribution studies in recurrent GBM patients undergoing surgery.
    RESULTS: As separate cohorts, MTD for concurrent adavosertib with RT/TMZ was 200 mg daily M-F x 6 weeks during RT and for adjuvant adavosertib with TMZ was 425 mg daily for 5 days of each 28-day cycle. However, 6/12 patients experienced DLTs in the combination cohort. The mean ratio of the intratumoral-to-plasma concentration of adavosertib was 4.18 ± 3.36 for contrast-enhancing tissue and 0.74 ± 0.63 in non-enhancing tissue.
    CONCLUSIONS: Adavosertib 200 mg daily M-F x 6 weeks with RT/TMZ and 425 mg daily on a 5d/28d cycle with TMZ had an unacceptable DLT rate. Additional dose levels in combination cohorts resulted in DLTs and we deemed concurrent adavosertib too toxic for further examination. Adavosertib 425 mg daily on a 5d/28d cycle with adjuvant TMZ is the recommended phase II dose. Tissue PK in tissue homogenates and by microdialysis provided complementary information about drug penetration.
    DOI:  https://doi.org/10.1158/1078-0432.CCR-24-2311
  5. Science. 2025 Jan 17. 387(6731): eabm5214
    Distinct myeloid-derived suppressor cell populations in human glioblastoma.
    Christina Jackson, Christopher Cherry, Sadhana Bom, Arbor G Dykema, Rulin Wang, Elizabeth Thompson, Ming Zhang, Runzhe Li, Zhicheng Ji, Wenpin Hou, Wentao Zhan, Hao Zhang, John Choi, Ajay Vaghasia, Landon Hansen, William Wang, Brandon Bergsneider, Kate M Jones, Fausto Rodriguez, Jon Weingart, Calixto-Hope Lucas, Jonathan Powell, Jennifer Elisseeff, Srinivasan Yegnasubramanian, Michael Lim, Chetan Bettegowda, Hongkai Ji, Drew Pardoll.
      The role of glioma-associated myeloid cells in tumor growth and immune evasion remains poorly understood. We performed single-cell RNA sequencing of immune and tumor cells from 33 gliomas, identifying two distinct myeloid-derived suppressor cell (MDSC) populations in isocitrate dehydrogenase-wild-type (IDT-WT) glioblastoma: an early progenitor MDSC (E-MDSC) population with up-regulation of metabolic and hypoxia pathways and a monocytic MDSC (M-MDSC) population. Spatial transcriptomics demonstrated that E-MDSCs geographically colocalize with metabolic stem-like tumor cells in the pseudopalisading region. Ligand-receptor analysis revealed cross-talk between these cells, where glioma stem-like cells produce chemokines attracting E-MDSCs, which in turn produce growth factors for the tumor cells. This interaction is absent in IDH-mutant gliomas, associated with hypermethylation and repressed gene expression of MDSC-attracting chemokines. Our study elucidates specific MDSCs that may facilitate glioblastoma progression and mediate tumor immunosuppression.
    DOI:  https://doi.org/10.1126/science.abm5214
  6. Nat Rev Drug Discov. 2025 Jan 10.
    Human brain organoids identify glioma inhibitors.
    Sarah Crunkhorn.
      
    DOI:  https://doi.org/10.1038/d41573-025-00007-z
  7. Acta Neuropathol Commun. 2025 Jan 11. 13(1): 6
    Personalising glioblastoma medicine: explant organoid applications, challenges and future perspectives.
    Niclas Skarne, Rochelle C J D'Souza, Helen M Palethorpe, Kylah A Bradbrook, Guillermo A Gomez, Bryan W Day.
      Glioblastoma (GBM) is a highly aggressive adult brain cancer, characterised by poor prognosis and a dismal five-year survival rate. Despite significant knowledge gains in tumour biology, meaningful advances in patient survival remain elusive. The field of neuro-oncology faces many disease obstacles, one being the paucity of faithful models to advance preclinical research and guide personalised medicine approaches. Recent technological developments have permitted the maintenance, expansion and cryopreservation of GBM explant organoid (GBO) tissue. GBOs represent a translational leap forward and are currently the state-of-the-art in 3D in vitro culture system, retaining brain cancer heterogeneity, and transiently maintaining the immune infiltrate and tumour microenvironment (TME). Here, we provide a review of existing brain cancer organoid technologies, in vivo xenograft approaches, evaluate in-detail the key advantages and limitations of this rapidly emerging technology, and consider solutions to overcome these difficulties. GBOs currently hold significant promise, with the potential to emerge as the key translational tool to synergise and enhance next-generation omics efforts and guide personalised medicine approaches for brain cancer patients into the future.
    Keywords:  Brain cancer; Explants; Glioblastoma; Heterogeneity; Organoids; Patient-derived; Personalised medicine
    DOI:  https://doi.org/10.1186/s40478-025-01928-x
  8. Sci Adv. 2025 Jan 17. 11(3): eadq5816
    Amphiphilic hemicyanine molecular probes crossing the blood-brain barrier for intracranial optical imaging of glioblastoma.
    Wei Qin, Honghui Li, Jiali Chen, Yang Qiu, Limin Ma, Liming Nie.
      Intracranial optical imaging of glioblastoma (GBM) is challenging due to the scarcity of effective probes with blood-brain barrier (BBB) permeability and sufficient imaging depth. Herein, we describe a rational strategy for designing optical probes crossing the BBB based on an electron donor-π-acceptor system to adjust the lipid/water partition coefficient and molecular weight of probes. The amphiphilic hemicyanine dye (namely, IVTPO), which exhibits remarkable optical properties and effective BBB permeability, is chosen as an efficient fluorescence/photoacoustic probe for in vivo real-time imaging of orthotopic GBM with high resolution through the intact skull. Abnormal leakage of IVTPO adjacent to the developing tumor is unambiguously observed at an early stage of tumor development prior to impairment of BBB integrity, as assessed by commercial Evans blue (EB). Compared with EB, IVTPO demonstrates enhanced optical imaging capability and improved tumor-targeting efficacy. These results offer encouraging insights into medical diagnosis of intracranial GBM.
    DOI:  https://doi.org/10.1126/sciadv.adq5816
  9. Neuro Oncol. 2025 Jan 11. pii: noaf005. [Epub ahead of print]
    Tracing tumor-neuronal connectivity in glioblastoma.
    Sean E Lawler.
      
    DOI:  https://doi.org/10.1093/neuonc/noaf005
  10. Neuro Oncol. 2025 Jan 11. pii: noaf008. [Epub ahead of print]
    Disease stage-specific role of the mitochondrial pyruvate carrier suppresses differentiation in temozolomide and radiation-treated glioblastoma.
    Emma Martell, Helgi Kuzmychova, Harshal Senthil, Ujala Chawla, Esha Kaul, Akaljot Grewal, Versha Banerji, Christopher M Anderson, Chitra Venugopal, Donald Miller, Tamra E Werbowetski-Ogilvie, Sheila K Singh, Tanveer Sharif.
       BACKGROUND: The mitochondrial pyruvate carrier (MPC), a central metabolic conduit linking glycolysis and mitochondrial metabolism, is instrumental in energy production. However, the role of the MPC in cancer is controversial. In particular, the importance of the MPC in glioblastoma (GBM) disease progression following standard temozolomide (TMZ) and radiation therapy (RT) remains unexplored.
    METHODS: Leveraging in vitro and in vivo patient-derived models of TMZ-RT treatment in GBM, we characterize the temporal dynamics of MPC abundance and downstream metabolic consequences using state-of-the-art molecular, metabolic, and functional assays.
    RESULTS: Our findings unveil a disease stage-specific role for the MPC, where in post-treatment GBM, but not therapy-naïve tumors, the MPC acts as a central metabolic regulator that suppresses differentiation. Temporal profiling reveals a dynamic metabolic rewiring where a steady increase in MPC abundance favors a shift towards enhanced mitochondrial metabolic activity across patient GBM samples. Intriguingly, while overall mitochondrial metabolism is increased, acetyl-CoA production is reduced in post-treatment GBM cells, hindering histone acetylation and silencing neural differentiation genes in an MPC-dependent manner. Finally, the therapeutic translations of these findings are highlighted by the successful pre-clinical patient-derived orthotopic xenograft (PDOX) trials utilizing a blood-brain-barrier (BBB) permeable MPC inhibitor, MSDC-0160, which augments standard TMZ-RT therapy to mitigate disease relapse and prolong animal survival.
    CONCLUSION: Our findings demonstrate the critical role of the MPC in mediating GBM aggressiveness and molecular evolution following standard TMZ-RT treatment, illuminating a therapeutically-relevant metabolic vulnerability to potentially improve survival outcomes for GBM patients.
    Keywords:  Glioblastoma; differentiation; metabolism; mitochondrial pyruvate carrier; tumor recurrence
    DOI:  https://doi.org/10.1093/neuonc/noaf008
  11. F1000Res. 2024 ;13 1361
    Analysis of Circulating Plasma MicroRNA Profile in Low-Grade and High-Grade Glioma - A Cross-Sectional Study.
    Ery Kus Dwianingsih, Rachmat Andi Hartanto, Sekar Safitri, Yeshua Putra Krisnugraha, Christina Megawimanti Sianipar, Endro Basuki, Kusumo Dananjoyo, Ahmad Asmedi, Bo Sun, Rusdy Ghazali Malueka.
       Background: Glioma is the second most common type of brain tumor, accounting for 24% of all brain tumor cases. The current diagnostic procedure is through an invasive tissue sampling to obtain histopathological analysis, however, not all patients are able to undergo a high-risk procedure. Circulating microRNAs (miRNAs) are considered as promising biomarkers for glioma due to their sensitivity, specificity, and non-invasive properties. There is currently no defined miRNA profile that contributes to determining the grade of glioma. This study aims to find the answer for "Is there any significant miRNA that able to distinguish different grades of glioma?".
    Methods: This study was conducted to compare the expression of miRNAs between low-grade glioma (LGG) and high-grade glioma (HGG). Eighteen blood plasma samples from glioma patients and 6 healthy controls were analyzed for 798 human miRNA profiles using NanoString nCounter Human v3 miRNA Expression Assay. The differential expressions of miRNAs were then analyzed to identify the differences in miRNA expression between LGG and HGG.
    Results: Analyses showed significant expressions in 12 miRNAs between LGG and HGG, where all of them were downregulated. Out of these significant miRNAs, miR-518b, miR-1271-3p, and miR-598-3p showed the highest potential for distinguishing HGG from LGG, with area under curve (AUC) values of 0.912, 0.889, and 0.991, respectively.
    Conclusion: miR-518b, miR-1271-3p, and miR-598-3p demonstrate significant potentials in distinguishing LGG and HGG.
    Keywords:  Glioma; grade; circulating miRNA; blood plasma; NanoString; biomarker
    DOI:  https://doi.org/10.12688/f1000research.153731.1
  12. Nat Commun. 2025 Jan 14. 16(1): 658
    Genetic predisposition to altered blood cell homeostasis is associated with glioma risk and survival.
    Linda Kachuri, Geno A Guerra, Taishi Nakase, George A Wendt, Helen M Hansen, Annette M Molinaro, Paige Bracci, Lucie McCoy, Terri Rice, John K Wiencke, Jeanette E Eckel-Passow, Robert B Jenkins, Margaret Wrensch, Stephen S Francis.
      Glioma is a highly fatal and heterogeneous brain tumor with few known risk factors. Our study examines genetically predicted variability in blood cell indices in relation to glioma risk and survival in 3418 cases and 8156 controls. We find that increased platelet to lymphocyte ratio (PLR) confers an increased risk of glioma (odds ratio (OR) = 1.25, p = 0.005), especially tumors with isocitrate dehydrogenase (IDH) mutations (OR = 1.38, p = 0.007) and IDHmut 1p/19q intact (IDHmut-intact OR = 1.53, p = 0.004) tumors. Genetically inferred increased counts of lymphocytes (IDHmut-intact OR = 0.70, p = 0.004) and neutrophils (IDHmut OR = 0.69, p = 0.019; IDHmut-intact OR = 0.60, p = 0.009) show inverse associations with risk, which may reflect enhanced immune-surveillance. Considering survival, we observe higher mortality risk in patients with IDHmut 1p/19q with genetically predicted increased counts of lymphocytes (hazard ratio (HR) = 1.65, 95% CI: 1.24-2.20), neutrophils (HR = 1.49, 1.13-1.97), and eosinophils (HR = 1.59, 1.18-2.14). Polygenic scores for blood cell traits are also differentially associated with 17 tumor immune microenvironment features in a subtype-specific manner, including signatures related to interferon signaling, PD-1 expression, and T-cell/Cytotoxic responses. Our findings highlight immune-mediated susceptibility mechanisms with potential disease management implications.
    DOI:  https://doi.org/10.1038/s41467-025-55919-6
  13. Nature. 2025 Jan 16.
    Brain-wide neuronal circuit connectome of human glioblastoma.
    Yusha Sun, Xin Wang, Daniel Y Zhang, Zhijian Zhang, Janardhan P Bhattarai, Yingqi Wang, Kristen H Park, Weifan Dong, Yun-Fen Hung, Qian Yang, Feng Zhang, Keerthi Rajamani, Shang Mu, Benjamin C Kennedy, Yan Hong, Jamie Galanaugh, Abhijeet Sambangi, Sang Hoon Kim, Garrett Wheeler, Tiago Gonçalves, Qing Wang, Daniel Geschwind, Riki Kawaguchi, Angela N Viaene, Ingo Helbig, Sudha K Kessler, Ahmet Hoke, Huadong Wang, Fuqiang Xu, Zev A Binder, H Isaac Chen, Emily Ling-Lin Pai, Sara Stone, MacLean P Nasrallah, Kimberly M Christian, Marc Fuccillo, Nicolas Toni, Zhuhao Wu, Hwai-Jong Cheng, Donald M O'Rourke, Minghong Ma, Guo-Li Ming, Hongjun Song.
      Glioblastoma (GBM) infiltrates the brain and can be synaptically innervated by neurons, which drives tumor progression1,2. Synaptic inputs onto GBM cells identified so far are largely short-range and glutamatergic3,4. The extent of GBM integration into the brain-wide neuronal circuitry remains unclear. Here we applied rabies virus- and herpes simplex virus-mediated trans-monosynaptic tracing5,6 to systematically investigate circuit integration of human GBM organoids transplanted into adult mice. We found that GBM cells from multiple patients rapidly integrate into diverse local and long-range neural circuits across the brain. Beyond glutamatergic inputs, we identified various neuromodulatory inputs, including synapses between basal forebrain cholinergic neurons and GBM cells. Acute acetylcholine stimulation induces long-lasting elevation of calcium oscillations and transcriptional reprogramming of GBM cells into a more motile state via the metabotropic CHRM3 receptor. CHRM3 activation promotes GBM cell motility, whereas its downregulation suppresses GBM cell motility and prolongs mouse survival. Together, these results reveal the striking capacity for human GBM cells to rapidly and robustly integrate into anatomically diverse neuronal networks of different neurotransmitter systems. Our findings further support a model wherein rapid connectivity and transient activation of upstream neurons may lead to a long-lasting increase in tumor fitness.
    DOI:  https://doi.org/10.1038/s41586-025-08634-7
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