bims-malgli Biomed News
on Biology of malignant gliomas
Issue of 2023–02–19
thirteen papers selected by
Oltea Sampetrean, Keio University
  1. Circadian regulator CLOCK promotes tumor angiogenesis in glioblastoma.
  2. Pleiotropic effects of the COX-2/PGE2 axis in the glioblastoma tumor microenvironment.
  3. RUNX1/CD44 axis regulates the proliferation, migration, and immunotherapy of gliomas: A single-cell sequencing analysis.
  4. PRMT6-CDC20 facilitates glioblastoma progression via the degradation of CDKN1B.
  5. Sorting-nexin-10 sustains platelet-derived growth factor receptor signaling in glioblastoma stem cells via endosomal protein sorting.
  6. Development and validation of an advanced ex vivo brain slice invasion assay to model glioblastoma cell invasion into the complex brain microenvironment.
  7. Phase 2 trials in the era of glioblastoma immunotherapy: New mechanisms of action, familiar challenges in trial design and tumor response assessment.
  8. Phenotyping clonal populations of glioma stem cell reveals a high degree of plasticity in response to changes of microenvironment.
  9. Chronotherapy in Glioblastoma: State of the art and future perspectives.
  10. T cell-independent eradication of experimental glioma by intravenous TLR7/8-agonist-loaded nanoparticles.
  11. ALK amplification and rearrangements are recurrent targetable events in congenital and adult glioblastoma.
  12. Utility of real-time polymerase chain reaction for the assessment of CDKN2A homozygous deletion in adult-type IDH-mutant astrocytoma.
  13. Glioma epileptiform activity and progression are driven by IGSF3-mediated potassium dysregulation.
  1. Cell Rep. 2023 Feb 14. pii: S2211-1247(23)00138-9. [Epub ahead of print]42(2): 112127
    Circadian regulator CLOCK promotes tumor angiogenesis in glioblastoma.
    Lizhi Pang, Madeline Dunterman, Wenjing Xuan, Annette Gonzalez, Yiyun Lin, Wen-Hao Hsu, Fatima Khan, Robert S Hagan, William A Muller, Amy B Heimberger, Peiwen Chen.
      Glioblastoma (GBM) is one of the most aggressive tumors in the adult central nervous system. We previously revealed that circadian regulation of glioma stem cells (GSCs) affects GBM hallmarks of immunosuppression and GSC maintenance in a paracrine and autocrine manner. Here, we expand the mechanism involved in angiogenesis, another critical GBM hallmark, as a potential basis underlying CLOCK's pro-tumor effect in GBM. Mechanistically, CLOCK-directed olfactomedin like 3 (OLFML3) expression results in hypoxia-inducible factor 1-alpha (HIF1α)-mediated transcriptional upregulation of periostin (POSTN). As a result, secreted POSTN promotes tumor angiogenesis via activation of the TANK-binding kinase 1 (TBK1) signaling in endothelial cells. In GBM mouse and patient-derived xenograft models, blockade of the CLOCK-directed POSTN-TBK1 axis inhibits tumor progression and angiogenesis. Thus, the CLOCK-POSTN-TBK1 circuit coordinates a key tumor-endothelial cell interaction and represents an actionable therapeutic target for GBM.
    Keywords:  BMAL1; CLOCK; CP: Cancer; TBK1; and POSTN; angiogenesis; circadian rhythm; glioblastoma; tumor microenvironment
    DOI:  https://doi.org/10.1016/j.celrep.2023.112127
  2. Front Oncol. 2022 ;12 1116014
    Pleiotropic effects of the COX-2/PGE2 axis in the glioblastoma tumor microenvironment.
    Phillip T Dean, Shelley B Hooks.
      Glioblastoma (GBM) is the most common and aggressive form of malignant glioma. The GBM tumor microenvironment (TME) is a complex ecosystem of heterogeneous cells and signaling factors. Glioma associated macrophages and microglia (GAMs) constitute a significant portion of the TME, suggesting that their functional attributes play a crucial role in cancer homeostasis. In GBM, an elevated GAM population is associated with poor prognosis and therapeutic resistance. Neoplastic cells recruit these myeloid populations through release of chemoattractant factors and dysregulate their induction of inflammatory programs. GAMs become protumoral advocates through production a variety of cytokines, inflammatory mediators, and growth factors that can drive cancer proliferation, invasion, immune evasion, and angiogenesis. Among these inflammatory factors, cyclooxygenase-2 (COX-2) and its downstream product, prostaglandin E2 (PGE2), are highly enriched in GBM and their overexpression is positively correlated with poor prognosis in patients. Both tumor cells and GAMs have the ability to signal through the COX-2 PGE2 axis and respond in an autocrine/paracrine manner. In the GBM TME, enhanced signaling through the COX-2/PGE2 axis leads to pleotropic effects that impact GAM dynamics and drive tumor progression.
    Keywords:  COX-2; PGE2; cancer; glioblastoma; inflammation; macrophage; microglia; tumor microenvironment
    DOI:  https://doi.org/10.3389/fonc.2022.1116014
  3. Front Immunol. 2023 ;14 1086280
    RUNX1/CD44 axis regulates the proliferation, migration, and immunotherapy of gliomas: A single-cell sequencing analysis.
    Hao Zhang, Hui Cao, Hong Luo, Nan Zhang, Zeyu Wang, Ziyu Dai, Wantao Wu, Guodong Liu, Zongyi Xie, Quan Cheng, Yuan Cheng.
       Background: Glioma is one of the most common, primary, and lethal adult brain tumors because of its extreme aggressiveness and poor prognosis. Several recent studies relevant to the immune function of CD44, a transmembrane glycoprotein as a significant hyaluronic acid receptor, have achieved great success, revealing the critical role of CD44 in immune infiltration in gliomas. The overexpression of CD44 has been verified to correlate with cancer aggressiveness and migration, while the clinical and immune features of CD44 expression have not yet been thoroughly characterized in gliomas.
    Methods: Molecular and clinical data of glioma collected from publicly available genomic databases were analyzed.
    Results: CD44 was up-expressed in malignant gliomas, notably in the 1p/19q non-codeletion cases, isocitrate dehydrogenase (IDH) wild-type, and mesenchymal subtypes in GBM samples. CD44 expression level strongly correlates with stromal and immune cells, mainly infiltrating the glioma microenvironment by single-cell sequencing analysis. Meanwhile, CD44 can be a promising biomarker in predicting immunotherapy responses and mediating the expression of PD-L1. Finally, RUNX1/CD44 axis could promote the proliferation and migration of gliomas.
    Conclusions: Therefore, CD44 was responsible for glioma growth and progression. It could potentially lead to a novel target for glioma immunotherapy or a prognostic biomarker.
    Keywords:  CD44; PD-L1; RUNX1; glioma; immunotherapy
    DOI:  https://doi.org/10.3389/fimmu.2023.1086280
  4. Oncogene. 2023 Feb 15.
    PRMT6-CDC20 facilitates glioblastoma progression via the degradation of CDKN1B.
    Ji Wang, Zongyu Xiao, Peng Li, Chunwang Wu, Yan Li, Qing Wang, Yanming Chen, Honglong Zhou, Zhi Li, Zhaotao Wang, Qing Lan, Yezhong Wang.
      PRMT6, a type I arginine methyltransferase, di-methylates the arginine residues of both histones and non-histones asymmetrically. Increasing evidence indicates that PRMT6 plays a tumor mediator involved in human malignancies. Here, we aim to uncover the essential role and underlying mechanisms of PRMT6 in promoting glioblastoma (GBM) proliferation. Investigation of PRMT6 expression in glioma tissues demonstrated that PRMT6 is overexpressed, and elevated expression of PRMT6 is negatively correlated with poor prognosis in glioma/GBM patients. Silencing PRMT6 inhibited GBM cell proliferation and induced cell cycle arrest at the G0/G1 phase, while overexpressing PRMT6 had opposite results. Further, we found that PRMT6 attenuates the protein stability of CDKN1B by promoting its degradation. Subsequent mechanistic investigations showed that PRMT6 maintains the transcription of CDC20 by activating histone methylation mark (H3R2me2a), and CDC20 interacts with and destabilizes CDKN1B. Rescue experimental results confirmed that PRMT6 promotes the ubiquitinated degradation of CDKN1B and cell proliferation via CDC20. We also verified that the PRMT6 inhibitor (EPZ020411) could attenuate the proliferative effect of GBM cells. Our findings illustrate that PRMT6, an epigenetic mediator, promotes CDC20 transcription via H3R2me2a to mediate the degradation of CDKN1B to facilitate GBM progression. Targeting PRMT6-CDC20-CDKN1B axis might be a promising therapeutic strategy for GBM.
    DOI:  https://doi.org/10.1038/s41388-023-02624-7
  5. JCI Insight. 2023 Feb 16. pii: e158077. [Epub ahead of print]
    Sorting-nexin-10 sustains platelet-derived growth factor receptor signaling in glioblastoma stem cells via endosomal protein sorting.
    Ryan C Gimple, Guoxin Zhang, Shuai Wang, Tengfei Huang, Jina Lee, Suchet Taori, Deguan Lv, Deobrat Dixit, Matthew E Halbert, Andrew R Morton, Reilly L Kidwell, Zhen Dong, Briana C Prager, Leo Kim, Zhixin Qiu, Linjie Zhao, Qi Xie, Qiulian Wu, Sameer Agnihotri, Jeremy N Rich.
      Glioblastoma is the most malignant primary brain tumor for which the prognosis remains dismal even with aggressive surgical, medical, and radiation therapies. Glioblastoma stem cells (GSCs) promote therapeutic resistance and cellular heterogeneity due to their self-renewal properties and capacity for plasticity. To understand the molecular processes essential for maintaining GSCs, we performed an integrative analysis comparing active enhancer landscapes, transcriptional profiles, and functional genomics profiles of GSCs and non-neoplastic neural stem cells (NSCs). We identified sorting nexin 10 (SNX10), an endosomal protein sorting factor, as selectively expressed in GSCs compared to NSCs and essential for GSC survival. Targeting SNX10 impaired GSC viability and proliferation, induced apoptosis, and reduced self-renewal capacity. Mechanistically, GSCs utilized endosomal protein sorting to promote platelet-derived growth factor receptor β (PDGFRβ) proliferative and stem cell signaling pathways through post-transcriptional regulation of the PDGFR tyrosine kinase. Targeting SNX10 expression extended survival of orthotopic xenograft-bearing mice, and high SNX10 expression correlated with poor glioblastoma patient prognosis, suggesting its potential clinical importance. Thus, our study reveals an essential connection between endosomal protein sorting and oncogenic receptor tyrosine kinase signaling and suggests that targeting endosomal sorting may represent a promising therapeutic approach for glioblastoma treatment.
    Keywords:  Brain cancer; Epigenetics; Growth factors; Oncology; Stem cells
    DOI:  https://doi.org/10.1172/jci.insight.158077
  6. Front Oncol. 2023 ;13 976945
    Development and validation of an advanced ex vivo brain slice invasion assay to model glioblastoma cell invasion into the complex brain microenvironment.
    Lisa R Decotret, Rocky Shi, Kiersten N Thomas, Manchi Hsu, Catherine J Pallen, Kevin L Bennewith.
      Organotypic cultures of murine brain slices are well-established tools in neuroscience research, including electrophysiology studies, modeling neurodegeneration, and cancer research. Here, we present an optimized ex vivo brain slice invasion assay that models glioblastoma multiforme (GBM) cell invasion into organotypic brain slices. Using this model, human GBM spheroids can be implanted with precision onto murine brain slices and cultured ex vivo to allow tumour cell invasion into the brain tissue. Traditional top-down confocal microscopy allows for imaging of GBM cell migration along the top of the brain slice, but there is limited resolution of tumour cell invasion into the slice. Our novel imaging and quantification technique involves embedding stained brain slices into an agar block, re-sectioning the slice in the Z-direction onto slides, and then using confocal microscopy to image cellular invasion into the brain tissue. This imaging technique allows for the visualization of invasive structures beneath the spheroid that would otherwise go undetected using traditional microscopy approaches. Our ImageJ macro (BraInZ) allows for the quantification of GBM brain slice invasion in the Z-direction. Importantly, we note striking differences in the modes of motility observed when GBM cells invade into Matrigel in vitro versus into brain tissue ex vivo highlighting the importance of incorporating the brain microenvironment when studying GBM invasion. In summary, our version of the ex vivo brain slice invasion assay improves upon previously published models by more clearly differentiating between migration along the top of the brain slice versus invasion into the slice.
    Keywords:  brain microenvironment; confocal microscopy; glioblastoma multiforme; invasion; metastasis; organotypic brain slice culture
    DOI:  https://doi.org/10.3389/fonc.2023.976945
  7. Neuro Oncol. 2023 Feb 15. pii: noad043. [Epub ahead of print]
    Phase 2 trials in the era of glioblastoma immunotherapy: New mechanisms of action, familiar challenges in trial design and tumor response assessment.
    Stephen J Bagley.
      
    DOI:  https://doi.org/10.1093/neuonc/noad043
  8. Lab Invest. 2022 02;pii: S0023-6837(22)00079-4. [Epub ahead of print]102(2): 172-184
    Phenotyping clonal populations of glioma stem cell reveals a high degree of plasticity in response to changes of microenvironment.
    James A Innes, Andrew S Lowe, Raquel Fonseca, Natasha Aley, Tedani El-Hassan, Myrianni Constantinou, Joanne Lau, Ayad Eddaoudi, Silvia Marino, Sebastian Brandner.
      The phenotype of glioma-initiating cells (GIC) is modulated by cell-intrinsic and cell-extrinsic factors. Phenotypic heterogeneity and plasticity of GIC is an important limitation to therapeutic approaches targeting cancer stem cells. Plasticity also presents a challenge to the identification, isolation, and propagation of purified cancer stem cells. Here we use a barcode labelling approach of GIC to generate clonal populations over a number of passages, in combination with phenotyping using the established stem cell markers CD133, CD15, CD44, and A2B5. Using two cell lines derived from isocitrate dehydrogenase (IDH)-wildtype glioblastoma, we identify a remarkable heterogeneity of the phenotypes between the cell lines. During passaging, clonal expansion manifests as the emergence of a limited number of barcoded clones and a decrease in the overall number of clones. Dual-labelled GIC are capable of forming traceable clonal populations which emerge after as few as two passages from mixed cultures and through analyses of similarity of relative proportions of 16 surface markers we were able to pinpoint the fate of such populations. By generating tumour organoids we observed a remarkable persistence of dominant clones but also a significant plasticity of stemness marker expression. Our study presents an experimental approach to simultaneously barcode and phenotype glioma-initiating cells to assess their functional properties, for example to screen newly established GIC for tumour-specific therapeutic vulnerabilities. The authors barcoded glioma-initiating cells (GIC) using combinations of virally encoded fluorophores. GIC show a strong tendency to form clonal populations over as few as two passages. Combined with stem cell marker phenotyping and computational analysis, they could trace the fate of such populations. This model presents an approach for rapid assessment of newly established GIC to assess tumour-specific vulnerabilities.
    DOI:  https://doi.org/10.1038/s41374-021-00695-2
  9. EBioMedicine. 2023 Feb 14. pii: S2352-3964(23)00035-X. [Epub ahead of print]89 104470
    Chronotherapy in Glioblastoma: State of the art and future perspectives.
    Marina Petković, Melad Henis, Oliver Heese, Angela Relógio.
      Circadian rhythms regulate various processes in the human body, including drug metabolism. Chronotherapy optimizes treatment timing based on the circadian rhythm of the individual patient, such that the treatment efficacy is maximized, and adverse effects are minimized. It has been explored in different cancers with varying conclusions. Glioblastoma multiforme (GBM) is the most aggressive type of brain tumour with a very dismal prognosis. In recent years, there has been very little success in designing successful therapies to fight this disease. Chronotherapy offers the opportunity to leverage existing treatments to extend patient survival and to increase their quality of life. Here, we discuss recent advances in using chronotherapy regimens in the treatment of GMB, such as radiotherapy, temozolomide (TMZ) and bortezomib, as well as discuss novel treatments with drugs of short half-life or circadian phase specific activity, and examine the therapeutic potential of new approaches that target elements of the core circadian clock.
    Keywords:  Brain cancer; Chronotherapy; Circadian medicine; Circadian rhythm; Glioblastoma; Glioma
    DOI:  https://doi.org/10.1016/j.ebiom.2023.104470
  10. Nat Commun. 2023 Feb 11. 14(1): 771
    T cell-independent eradication of experimental glioma by intravenous TLR7/8-agonist-loaded nanoparticles.
    Verena Turco, Kira Pfleiderer, Jessica Hunger, Natalie K Horvat, Kianush Karimian-Jazi, Katharina Schregel, Manuel Fischer, Gianluca Brugnara, Kristine Jähne, Volker Sturm, Yannik Streibel, Duy Nguyen, Sandro Altamura, Dennis A Agardy, Shreya S Soni, Abdulrahman Alsasa, Theresa Bunse, Matthias Schlesner, Martina U Muckenthaler, Ralph Weissleder, Wolfgang Wick, Sabine Heiland, Philipp Vollmuth, Martin Bendszus, Christopher B Rodell, Michael O Breckwoldt, Michael Platten.
      Glioblastoma, the most common and aggressive primary brain tumor type, is considered an immunologically "cold" tumor with sparse infiltration by adaptive immune cells. Immunosuppressive tumor-associated myeloid cells are drivers of tumor progression. Therefore, targeting and reprogramming intratumoral myeloid cells is an appealing therapeutic strategy. Here, we investigate a β-cyclodextrin nanoparticle (CDNP) formulation encapsulating the Toll-like receptor 7 and 8 (TLR7/8) agonist R848 (CDNP-R848) to reprogram myeloid cells in the glioma microenvironment. We show that intravenous monotherapy with CDNP-R848 induces regression of established syngeneic experimental glioma, resulting in increased survival rates compared with unloaded CDNP controls. Mechanistically, CDNP-R848 treatment reshapes the immunosuppressive tumor microenvironment and orchestrates tumor clearing by pro-inflammatory tumor-associated myeloid cells, independently of T cells and NK cells. Using serial magnetic resonance imaging, we identify a radiomic signature in response to CDNP-R848 treatment and ultrasmall superparamagnetic iron oxide (USPIO) imaging reveals that immunosuppressive macrophage recruitment is reduced by CDNP-R848. In conclusion, CDNP-R848 induces tumor regression in experimental glioma by targeting blood-borne macrophages without requiring adaptive immunity.
    DOI:  https://doi.org/10.1038/s41467-023-36321-6
  11. Clin Cancer Res. 2023 Feb 13. pii: CCR-21-3521. [Epub ahead of print]
    ALK amplification and rearrangements are recurrent targetable events in congenital and adult glioblastoma.
    Anne-Florence Blandin, Ross Giglio, Maya Srikanth Graham, Guadalupe Garcia, Seth Malinowski, Jared K Woods, Shakti Ramkissoon, Lori Ramkissoon, Frank Dubois, Kathleen Schoolcraft, Jessica Tsai, Dayle Wang, Robert Jones, Jayne Vogelzang, Kristine Pelton, Sarah Becker, Fiona Watkinson, Claire Sinai, Elizabeth F Cohen, Matthew A Booker, Michael Y Tolstorukov, Veerle Haemels, Liliana Goumnerova, Karen Wright, Mark Kieran, Katie Fehnel, David Reardon, Arnault Tauziède-Espariat, Rishi Lulla, Benjamin Carcamo, Stanley Chaleff, Alain Charest, Frederik De Smet, Azra H Ligon, Adrian Dubuc, Melanie Pages, Pascale Varlet, Patrick Y Wen, Brian M Alexander, Susan Chi, Sanda Alexandrescu, Ralf Kittler, Robert Bachoo, Pratiti Bandopadhayay, Rameen Beroukhim, Keith L Ligon.
       PURPOSE: Anaplastic Lymphoma Kinase (ALK) aberrations have been identified in pediatric type infant gliomas, but their occurrence across age groups, functional effects, and treatment response have not been broadly established.
    EXPERIMENTAL DESIGN: We performed a comprehensive analysis of ALK expression and genomic aberrations in both newly generated and retrospective data from 371 glioblastomas (156 adult, 205 infant/pediatric and 10 congenital) with in vitro and in vivo validation of aberrations.
    RESULTS: ALK aberrations at the protein or genomic level were detected in 12% of gliomas (45/371) in a wide age range (0-80 years). Recurrent as well as novel ALK fusions (LRRFIP1-ALK, DCTN1-ALK, PRKD3-ALK) were present in 50% (5/10) of congenital/infant, 1.4% (3/205) of pediatric, and 1.9% (3/156) of adult GBMs. ALK fusions were present as the only candidate driver in congenital/infant GBMs and were sometimes focally amplified. In contrast, adult ALK fusions co-occurred with other oncogenic drivers. No activating ALK mutations were identified in any age group. Novel and recurrent ALK rearrangements promoted STAT3 and ERK1/2 pathways and transformation in vitro and in vivo.ALK-fused GBM cellular and mouse models were responsive to ALK inhibitors, including in patient cells derived from a congenital GBM. Relevant to treatment of infant gliomas, we showed that ALK protein appears minimally expressed in the forebrain at perinatal stages and no gross effects on perinatal brain development was seen in pregnant mice treated with the ALK inhibitor ceritinib.
    CONCLUSIONS: These findings support use of brain-penetrant ALK inhibitors in clinical trials across infant, pediatric, and adult GBMs.
    DOI:  https://doi.org/10.1158/1078-0432.CCR-21-3521
  12. Brain Tumor Pathol. 2023 Feb 14.
    Utility of real-time polymerase chain reaction for the assessment of CDKN2A homozygous deletion in adult-type IDH-mutant astrocytoma.
    Yuzaburo Shimizu, Mario Suzuki, Osamu Akiyama, Ikuko Ogino, Yuko Matsushita, Kaishi Satomi, Shunsuke Yanagisawa, Makoto Ohno, Masamichi Takahashi, Yasuji Miyakita, Yoshitaka Narita, Koichi Ichimura, Akihide Kondo.
      The World Health Organization Classification of Tumors of the Central Nervous System 5th Edition (WHO CNS5) introduced a newly defined astrocytoma, IDH-mutant grade 4, for adult diffuse glioma classification. One of the diagnostic criteria is the presence of a CDKN2A/B homozygous deletion (HD). Here, we report a robust and cost-effective quantitative polymerase chain reaction (qPCR)-based test for assessing CDKN2A HD. A TaqMan copy number assay was performed using a probe located within CDKN2A. The linear correlation between the Ct values and relative CDKN2A copy number was confirmed using a serial mixture of DNA from normal blood and U87MG cells. The qPCR assay was performed in 109 IDH-mutant astrocytomas, including 14 tumors with CDKN2A HD, verified either by multiplex ligation-dependent probe amplification (MLPA) or CytoScan HD microarray platforms. Receiver operating characteristic curve analysis indicated that a cutoff value of 0.85 yielded optimal sensitivity (100%) and specificity (99.0%) for determining CDKN2A HD. The assay applies to DNA extracted from frozen or formalin-fixed paraffin-embedded tissue samples. Survival was significantly shorter in patients with than in those without CDKN2A HD, assessed by either MLPA/CytoScan or qPCR. Thus, our qPCR method is clinically applicable for astrocytoma grading and prognostication, compatible with the WHO CNS5.
    Keywords:  Astrocytoma; CDKN2A; IDH; WHO classification; qPCR
    DOI:  https://doi.org/10.1007/s10014-023-00450-z
  13. Neuron. 2023 Feb 06. pii: S0896-6273(23)00037-5. [Epub ahead of print]
    Glioma epileptiform activity and progression are driven by IGSF3-mediated potassium dysregulation.
    Rachel Naomi Curry, Isamu Aiba, Jochen Meyer, Brittney Lozzi, Yeunjung Ko, Malcolm Ford McDonald, Anna Rosenbaum, Alexis Cervantes, Emmet Huang-Hobbs, Carolina Cocito, Jeffrey Peter Greenfield, Ali Jalali, Jay Gavvala, Carrie Mohila, Akdes Serin Harmanci, Jeffrey Noebels, Ganesh Rao, Benjamin Deneen.
      Seizures are a frequent pathophysiological feature of malignant glioma. Recent studies implicate peritumoral synaptic dysregulation as a driver of brain hyperactivity and tumor progression; however, the molecular mechanisms that govern these phenomena remain elusive. Using scRNA-seq and intraoperative patient ECoG recordings, we show that tumors from seizure patients are enriched for gene signatures regulating synapse formation. Employing a human-to-mouse in vivo functionalization pipeline to screen these genes, we identify IGSF3 as a mediator of glioma progression and dysregulated neural circuitry that manifests as spreading depolarization (SD). Mechanistically, we discover that IGSF3 interacts with Kir4.1 to suppress potassium buffering and found that seizure patients exhibit reduced expression of potassium handlers in proliferating tumor cells. In vivo imaging reveals that dysregulated synaptic activity emanates from the tumor-neuron interface, which we confirm in patients. Our studies reveal that tumor progression and seizures are enabled by ion dyshomeostasis and identify SD as a driver of disease.
    Keywords:  brain hyperactivity; glioma; glioma-related epilepsy; potassium dysregulation; spreading depolarization
    DOI:  https://doi.org/10.1016/j.neuron.2023.01.013
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