bims-malgli 2025-09-28 papers

bims-malgli

Biomed News

on Biology of malignant gliomas

Issue of 2025–09–28
fourteen papers selected by
Oltea Sampetrean, Keio University

Understanding proneural-mesenchymal transition using patient-derived glioma stem-like cell (GSC) organoids and engineered extracellular matrix.
Neuropeptide adrenomedullin remodels stemness and macrophage dynamics in glioblastoma.
JMJD6-driven epigenetic activation of COL4A2 reprograms glioblastoma vascularization via integrin α1β1-dependent PI3K/MAPK signaling.
Gain-of-function mutant p53 regulates long-noncoding RNA LINC00643 to modulate HIF1α in glioblastoma.
Ataxin-2 as a candidate blood biomarker for estimating disease status in cases of suspected glioblastoma recurrence.
Effect of focused ultrasound-induced mechanical ablation on stemness and dormancy properties of residual/peri-focally localized glioblastoma cells.
Targeting Glioblastoma Cell State Plasticity for Enhanced Therapeutic Efficacy.
Living on the edge: Uncommitted OPC-like cells drive glioblastoma invasiveness.
CDK12 regulates cellular metabolism to promote glioblastoma growth.
N6 -methyladenosine promotes temozolomide resistance through non-canonical regulation of mRNA stability in glioblastoma cells.
A Human Neuronal Co-Culture System Reveals Early Tumor-Neuron Communication and Targetable Pathways in Glioblastoma.
Targeting molecular vulnerabilities in glioblastoma.
Tumor heterogeneity underlies clinical outcome and MEK inhibitor response in somatic NF1-mutant glioblastoma.
Gliomas phenocopy an inborn error of metabolism to drive neuronal activity and tumor growth.

bioRxiv. 2025 Sep 20. pii: 2025.09.17.676829. [Epub ahead of print]

Understanding proneural-mesenchymal transition using patient-derived glioma stem-like cell (GSC) organoids and engineered extracellular matrix.

Autumn McManis, Charles Ashley Jimenez, Abha Shirolkar, Syed Raza Ur Rehman, Sumana Mallick, Malea Murphy, Akhilesh K Gaharwar, Irtisha Singh.

Glioblastoma multiforme (GBM) is a highly aggressive, angiogenic WHO grade IV glioma marked by rapid progression, therapeutic resistance, and poor prognosis. A defining feature of GBM is the presence of glioma stem-like cells (GSCs), which reside in specialized perivascular niches and drive tumor progression, recurrence, and therapeutic resistance. The blood-brain barrier, coupled with the complex and dynamic tumor microenvironment, poses significant challenges for both treatment and mechanistic investigation. Current in vitro GBM models inadequately recapitulate the structural and biochemical cues of the native perivascular niche due to the absence of functional vasculature and brain-mimetic extracellular matrix (ECM), limiting their physiological relevance and predictive power. To address the limitations of existing in vitro GBM models, we developed a patient-derived glioma stem cells (GSC) derived Matrigel spheroid system that transitions into organoids and enables integration into engineered microenvironments. Our model incorporates GSC organoids representing proneural and mesenchymal GBM subtypes, a synthetic engineered extracellular matrix (eECM), and endothelial cells (ECs) seeded on the matrix surface. We evaluated the expression of subtype-specific, pro-angiogenic, stemness, and differentiation markers under increasingly complex co-culture conditions. Our results show that Matrigel-derived GSC spheroids progressively differentiate into organoids over two weeks, with significantly enhanced expression of cell-specific markers in the presence of ECs. Encapsulation of these organoids within eECM, combined with EC co-culture, further promoted cellular invasion and induction of GBM associated genes. This in situ encapsulation strategy enables real-time observation of GSC behavior in a tunable microenvironment that mimics key features of the native tumor niche. Together, this platform provides a physiologically relevant and modular in vitro system for investigating GBM pathophysiology. It holds promise for uncovering tumor-specific cellular dependencies, studying GSC-vascular interactions, and conducting high-throughput drug screening under controlled, biomimetic conditions.
Significance: This study establishes a 3D GSC organoid model with engineered matrix to investigate glioblastoma plasticity and vascular mimicry.

DOI: https://doi.org/10.1101/2025.09.17.676829
Cell Rep. 2025 Sep 24. pii: S2211-1247(25)01113-1. [Epub ahead of print]44(10): 116342

Neuropeptide adrenomedullin remodels stemness and macrophage dynamics in glioblastoma.

Heba Ali, Fatima Khan, Wenjing Xuan, Yang Liu, Yuyun Huang, Donovan Whitfield, Lizhi Pang, Peiwen Chen.

  The presence of self-renewing glioblastoma (GBM) stem cells (GSCs) and infiltrating pro-tumor macrophages constitutes two key hallmarks of GBM. Here, we identified the neuropeptide adrenomedullin (ADM) as a key factor regulating GSC-macrophage symbiosis. Epidermal growth factor receptor (EGFR) overexpression upregulates ADM in GSCs to enhance their self-renewal, glycolysis, and tumor growth by activating the signal transducer and activator of transcription 3 (STAT3) pathway. GSC-secreted ADM promotes macrophage infiltration and pro-tumor reprogramming through activation of ADM receptor (ADMR), thereby engaging both STAT3 and STAT6 pathways. In GBM mouse and patient-derived xenograft (PDX) models, inhibition of the ADM-ADMR axis, STAT3, or STAT6 suppresses tumor progression, GSC self-renewal, and pro-tumor macrophage abundance, with dual inhibition of STAT3 and STAT6 leading to durable complete tumor regression in a subset of tumor-bearing mice. In human GBM tumors and plasmas, ADM correlates positively with GSC stemness, pro-tumor macrophage abundance, and poor prognosis. These findings highlight ADM-triggered GSC-macrophage symbiosis as a promising therapeutic target for GBM.

Keywords:  CP: Cancer; EGFR; STAT3; STAT6; adrenomedullin; glioblastoma; glioblastoma stem cells; glycolysis; macrophages; symbiosis

DOI:  https://doi.org/10.1016/j.celrep.2025.116342
Acta Neuropathol Commun. 2025 Sep 24. 13(1): 194

JMJD6-driven epigenetic activation of COL4A2 reprograms glioblastoma vascularization via integrin α1β1-dependent PI3K/MAPK signaling.

Yangyang Wu, Yanan Wu, Shuchou Xia, Hongkai Lian, Yongli Lou, Lin-Jian Wang.

  Glioblastoma multiforme (GBM), the most aggressive primary brain malignancy in adults, is characterized by extensive vascularization and resistance to conventional anti-angiogenic therapies. In this study, through comprehensive integrative analyses of bulk RNA-seq and single-cell RNA-seq data, we identify COL4A2 as a critical orchestrator of vascularization in GBM. Elevated COL4A2 not only promotes epithelial-mesenchymal transition (EMT) in glioma cells, but also increases vascularization in GBM. Multi-omics profiling and mechanistic investigations reveal that aberrant expression of the anti-pause enhancer JMJD6 mediates the upregulation of COL4A2 in GBM. Furthermore, we demonstrate that COL4A2 promotes GBM vascularization by activating PI3K-AKT and MAPK-ERK signaling through interaction with ITGA1/ITGB1 receptors on tumor-associated endothelial cells (TECs). Pharmacological inhibition of the COL4A2-ITGA1/ITGB1 axis with obtustatin attenuates pro-angiogenic signaling, suppresses vascularization, and prolongs survival in orthotopic GBM models. Collectively, our findings establish JMJD6-driven COL4A2-ITGA1/ITGB1 axis as a novel anti-angiogenic therapeutic vulnerability, offering a promising strategy to disrupt TEC-tumor symbiosis and impede GBM progression.

Keywords:  COL4A2; Glioblastoma multiforme; ITGA1/ITGB1; JMJD6; Tumor-associated endothelial cells; Vascularization

DOI:  https://doi.org/10.1186/s40478-025-02114-9
bioRxiv. 2025 Sep 18. pii: 2025.09.16.676559. [Epub ahead of print]

Gain-of-function mutant p53 regulates long-noncoding RNA LINC00643 to modulate HIF1α in glioblastoma.

Ying Zhang, Fang Yuan, Myron Keith Gibert, Collin Joseph Dube, Kadie Hudson, Cassandra Grello, Brian Reon, Shekhar Saha, Yunan Sun, Pawel Marcinkiewicz, Anindya Dutta, David Chief, Eric Holland, Roger Abounader.

Gain-of-function mutations of p53 (GOF-MUT-p53) act as oncogenes by regulating gene transcription. We screened for the genome-wide transcriptional targets of GOF-MUT-p53 in glioblastoma (GBM) and found that a significant subset of them were long non-coding RNAs (lncRNA). Among these, LINC00643 was strongly repressed by GOF-MUT-p53 but not wild-type p53. LINC00643 was downregulated in GBM and low-grade glioma and correlated with patient survival. LINC00643 and its conserved third exon (Exon3) suppressed GBM cell proliferation, migration, invasion, stem cell self-renewal, and in vivo tumor growth Mechanistically, ChIRP-seq identified HIF1α as a key LINC00643 interactor. Under hypoxia, LINC00643 repressed HIF1α expression and its target genes by interacting with the HIF1α enhancer. Knockdown of GOF-MUT-p53 upregulated LINC00643 and reduces HIF1α, revealing a regulatory axis. These findings show extensive regulation of lncRNAs by GOF-MUT-p53 and uncover a novel mechanism by which GOF-MUT-p53 drives GBM through repression of LINC00643 and dysregulation of the HIF1α pathway.

DOI: https://doi.org/10.1101/2025.09.16.676559
Brain Tumor Pathol. 2025 Sep 22.

Ataxin-2 as a candidate blood biomarker for estimating disease status in cases of suspected glioblastoma recurrence.

Farida Garaeva, Riho Nakajima, Sho Tamai, Kensuke Tateishi, Akitake Mukasa, Shinji Kawabata, Hiroaki Nagashima, Manabu Natsumeda, Nozomi Hirai, Shota Tanaka, Shigeo Ohba, Nayuta Higa, Yoshiki Arakawa, Akihide Kondo, Hidehiro Kohzuki, Shinichiro Koizumi, Yutaka Fujioka, Tatsuya Abe, Hemragul Sabit, Masashi Kinoshita, Yasuo Uchida, Sumio Ohtsuki, Mitsutoshi Nakada.

  Differentiating pseudoprogression (PsP) from recurrence in cases of glioblastoma (GBM) after chemoradiotherapy is challenging, with neuroimaging as the only non-invasive method. In this study, we aimed to identify a blood biomarker for precise disease monitoring and investigated the role of Ataxin-2 (ATXN2). Blood samples (n = 45) from patients with suspected recurrence, including eight with PSP, were analyzed. In addition, tumor tissue samples (n = 22), including those from seven patients who also provided blood samples, were examined. Protein levels were assessed using quantitative proteomics and ELISA. ATXN2 levels were measured via western blotting, and localization was determined through immunohistochemistry and immunocytochemistry. ATXN2 knockdown was performed in glioma cell lines to assess its effects on proliferation, migration, and invasion. Proteomics identified ATXN2 as a potential biomarker. ELISA showed significantly higher serum ATXN2 levels in recurrence than in PsP (p = 0.028). ATXN2 ≥ 11.0 ng/mL and ≥ 8 months post-chemoradiotherapy distinguished recurrence from PsP (AUC = 0.82, sensitivity = 67.6%, specificity = 87.5%). ATXN2 was highly expressed in GBM tissues, localized in neurons and glioma cells, and its knockdown enhanced proliferation, migration, and invasion via ERK phosphorylation. ATXN2, highly expressed in GBM, may serve as a potential blood biomarker for distinguishing PsP from recurrence.

Keywords:  Ataxin-2; Biomarker; Glioblastoma; Pseudoprogression; Recurrence

DOI:  https://doi.org/10.1007/s10014-025-00517-z
Neurooncol Adv. 2025 Jan-Dec;7(1):7(1): vdaf184

Effect of focused ultrasound-induced mechanical ablation on stemness and dormancy properties of residual/peri-focally localized glioblastoma cells.

Dana Hellmold, Levi Johanning, Jacqueline Clüver, Jonna Holler, Nils Oliver Schröder, Frieda Bayler, Hajrullah Ahmeti, Carolin Kubelt-Kwamin, Sina Wieker, Ann-Kristin Helmers, Michael Synowitz, Janka Held-Feindt.

   Background: Focused ultrasound (FUS) is a new technology that enables the spatially and temporally precise delivery of ultrasound energy to various targets. In addition to its known applications in treating tumors, cavitation-based mechanical focused ultrasound (mFUS) is gaining importance. Due to the novelty of this technique, little is known about the effects of mFUS on peri-focally localized or surviving tumor cells. Glioblastomas (GBMs) are highly malignant intracranial tumors with a pronounced intra- and intertumoral heterogeneity, which, eg leads to their evasion of appropriate treatment regimens.
Methods: The impact of mFUS was investigated in patient-derived GBM organoids (GBOs), glioma stem-like cells (GSCs), and differentiated GBM cells in an in vitro 3D hydrogel culture model. Particular attention was paid to investigating the stemness and dormancy properties of residual/peri-focally localized GBM cells, as these may be important for tumor progression.
Results: In GBOs and different primary cells, increased expression of dormancy- and stemness-associated markers was found in a complex region- and marker-dependent manner mediated via PI3-kinase/Akt/GSK3β signaling, suggesting an effect of mFUS beyond the focal area. mFUS resulted in an increased ability of residual/peri-focal, formerly differentiated patient-derived GBM cells to form stem cell-typical spheres associated with increased expression of various dormancy and stemness markers. Residual/peri-focal patient-derived cells were characterized by a higher resistance to temozolomide, resulting in fewer dead cells compared to temozolomide treatment alone.
Conclusion: The ablation of defined regions by mFUS appears to regulate the stemness and dormancy properties of the residual/peri-focally localized GBM cells in a region-specific manner.

Keywords:  dormancy; glioblastoma; mechanical focused ultrasound; stemness

DOI:  https://doi.org/10.1093/noajnl/vdaf184
bioRxiv. 2025 Sep 15. pii: 2025.09.08.674897. [Epub ahead of print]

Targeting Glioblastoma Cell State Plasticity for Enhanced Therapeutic Efficacy.

Stefano M Cirigliano, Richa Singhania, James Nicholson, Isha Monga, Yushan Wan, Caroline Haywood, Ashlesha Muley, Skylar Giacobetti, Howard A Fine.

Glioblastoma (GBM) is the most common and deadly primary brain cancer, with limited therapeutic options. Treatment failure has been associated with intratumoral heterogeneity and the acquisition of a pronounced mesenchymal-like (MES-L) phenotype after recurrence. Here, we have screened a panel of drugs with diverse mechanisms of action across two patient-derived glioblastoma stem cells (GSCs) to characterize the dynamics of drug-mediated transcriptomic cellular state changes. Our results demonstrate that anti-tumor drugs induce significant but reversible alterations in cellular state distribution at the single-cell level in a drug-specific manner, influencing transitions between mesenchymal and the neurodevelopmental astrocytic-like (AC-L) states. Utilizing barcoded analysis in our recently developed ex vivo glioblastoma cerebral organoid (GLICO) model, we discerned distinct cell state sensitivities to the MES-L enhancing histone deacetylase inhibitor, panobinostat, which are contingent on the inducible modulation of the mesenchymal transcription factor FOSL1. The strategic combination of MES-L enhancing and MES-l suppressing genetic perturbations or drugs significantly increases anti-glioma activity in a strategy we call state-selective lethality. Overall, our findings highlight the critical role of cell state plasticity in the response of GSCs to anti-tumor therapeutic stress and underscore the potential for novel GBM combination drug strategies.

DOI: https://doi.org/10.1101/2025.09.08.674897
Dev Cell. 2025 Sep 22. pii: S1534-5807(25)00502-7. [Epub ahead of print]60(18): 2383-2385

Living on the edge: Uncommitted OPC-like cells drive glioblastoma invasiveness.

Upendra K Soni, Q Richard Lu.

Glioblastoma invasion has been linked to mesenchymal states. However, in this issue of Developmental Cell, Wu et al. identify peritumoral, uncommitted oligodendrocyte progenitor-like cells as key invasive drivers that hijack neurodevelopmental programs to infiltrate the brain parenchyma, suggesting that targeting lineage differentiation and neuron-tumor networks may limit glioblastoma spread.

DOI: https://doi.org/10.1016/j.devcel.2025.08.002
JCI Insight. 2025 Sep 25. pii: e190780. [Epub ahead of print]

CDK12 regulates cellular metabolism to promote glioblastoma growth.

Jeong-Yeon Mun, Chang Shu, Qiuqiang Gao, Zhe Zhu, Hasan O Akman, Mike-Andrew Westhoff, Georg Karpel-Massler, Markus D Siegelin.

  Glioblastoma IDH-wildtype is the most common and aggressive primary brain tumor in adults, with poor prognosis despite current therapies. To identify new therapeutic vulnerabilities, we investigated the role of CDK12, a transcription-associated cyclin-dependent kinase, in glioblastoma. Genetic or pharmacologic inactivation of CDK12 impaired tumor growth in patientderived xenograft (PDX) models and enhanced the efficacy of temozolomide. Metabolic profiling using extracellular flux analysis and stable isotope tracing with U-¹³C-glucose and U-¹³Cglutamine showed that CDK12 inhibition disrupted mitochondrial respiration, resulting in energy depletion and apoptotic cell death characterized by caspase activation and Noxa induction. Mechanistically, we identified a direct interaction between CDK12 and GSK3β. CDK12 inhibition activated GSK3β, leading to downregulation of PPARD, a transcriptional regulator of oxidative metabolism. This CDK12-GSK3β-PPARD axis was required for glioblastoma cell proliferation and metabolic homeostasis. In vivo, CDK12 inhibition significantly extended survival without overt toxicity and induced complete tumor regression in a subset of animals. Strikingly, combined CDK12 inhibition and temozolomide treatment led to complete tumor eradication in all animals tested. These findings establish CDK12 as a key regulator of glioblastoma metabolism and survival, and provide strong preclinical rationale for its therapeutic targeting in combination with standard-of-care treatments.

Keywords:  Apoptosis; Brain cancer; Metabolism; Oncogenes; Oncology

DOI:  https://doi.org/10.1172/jci.insight.190780
bioRxiv. 2025 Sep 15. pii: 2025.09.14.676126. [Epub ahead of print]

N6 -methyladenosine promotes temozolomide resistance through non-canonical regulation of mRNA stability in glioblastoma cells.

Emily A Dangelmaier, Dorthy Fang, Kyal Sin Htet, Nicole S Harry, Renee Pascoe, Je Won Yang, Clara D Wang, Sigrid Nachtergaele.

N6 -methyladenosine (m 6 A) is a critical regulator of mRNA processing and function, impacting nearly every step of the mRNA lifecycle. Changes in m 6 A status have been implicated in many different types of cancer, including glioblastoma where acquired resistance to temozolomide remains a major clinical challenge. We established glioblastoma cell culture models of acquired temozolomide resistance and analyzed the role of m 6 A in controlling resistance-associated pathways. We show that m 6 A stabilizes key genes and pathways promoting temozolomide resistance in glioblastoma, including MGMT , the enzyme that repairs primary temzolomide-induced DNA damage, and PI3K/Akt signaling, a major driver of chemoresistance. Pharmacological inhibition of the m 6 A methyltransferase METTL3 destabilizes MGMT and other critical mRNAs, restoring temozolomide sensitivity. Collectively, our results suggest that genes associated with temozolomide resistance are stabilized by m 6 A methylation, even as the majority of the transcriptome remains subject to canonical m 6 A-mediated mRNA decay. Moreover, these data highlight METTL3 inhibition as a promising therapeutic approach to overcoming temozolomide resistance in glioblastoma.

DOI: https://doi.org/10.1101/2025.09.14.676126
bioRxiv. 2025 Sep 16. pii: 2025.09.10.675396. [Epub ahead of print]

A Human Neuronal Co-Culture System Reveals Early Tumor-Neuron Communication and Targetable Pathways in Glioblastoma.

Ouada Nebie, Niyi Adelakun, Liwen Zhang, Luke Kollin, Brian Fries, Akhil Medikonda, Monica Venere, Pierre Giglio, Nam Chu, Nhat T Le.

Glioblastoma (GB) co-opts neuronal circuits to drive tumor progression, yet the earliest neuronal responses that may shape recurrence remain poorly defined. We developed a human iPSC-derived neuronal co-culture model that captures acute communication between neurons and glioblastoma from diverse sources, including serum-adapted cell lines and patient-derived cells. Within 24 hours, glioma-exposed neurons exhibited synaptic remodeling and activation of tumor-associated signaling pathways. High-resolution imaging and proteomics revealed compartment-specific synaptic alterations, with ERK1/2 and p38 MAPK signaling differentially engaged depending on the tumor source, corresponding to distinct structural and functional outcomes. Pharmacologic inhibition of MAPK components both suppressed tumor cells growth and preserved neuronal integrity. By modeling source-dependent and early neuron-tumor interactions, this platform not only identifies MAPK signaling as a critical mediator of synaptic vulnerability but also provides a clinically relevant tool for investigating the mechanisms of glioblastoma recurrence. It offers a framework for developing therapies that target the dual vulnerabilities of tumor progression and circuit remodeling.

DOI: https://doi.org/10.1101/2025.09.10.675396
Nat Med. 2025 Sep 26.

Targeting molecular vulnerabilities in glioblastoma.

Joshua D Bernstock.

DOI: https://doi.org/10.1038/s41591-025-03952-9
JCI Insight. 2025 Sep 23. pii: e192658. [Epub ahead of print]10(18):

Tumor heterogeneity underlies clinical outcome and MEK inhibitor response in somatic NF1-mutant glioblastoma.

Sixuan Pan, Kanish Mirchia, Emily Payne, S John Liu, Nadeem Al-Adli, Zain Peeran, Poojan Shukla, Jacob S Young, Rohit Gupta, Jasper Wu, Joanna Pak, Tomoko Ozawa, Brian Na, Alyssa T Reddy, Steve E Braunstein, Joanna J Phillips, Susan Chang, David A Solomon, Arie Perry, David R Raleigh, Mitchel S Berger, Adam R Abate, Harish N Vasudevan.

  Tumor suppressor NF1 is recurrently mutated in glioblastoma, leading to aberrant activation of Ras/rapidly accelerated fibrosarcoma (RAF)/MEK signaling. However, how tumor heterogeneity shapes the molecular landscape and efficacy of targeted therapies remains unclear. Here, we combined bulk and single-cell genomics of human somatic NF1-mutant, isocitrate dehydrogenase (IDH) wild-type glioblastomas with functional studies in cell lines and mouse intracranial tumor models to identify mechanisms of tumor heterogeneity underlying clinical outcome and MEK inhibitor response. Targeted DNA sequencing identified CDKN2A/B homozygous deletion as a poor prognostic marker in somatic NF1-mutant, but not NF1 wild-type, glioblastoma. Single-nucleus RNA sequencing of human patient NF1-mutant glioblastomas demonstrated that mesenchymal-like (MES-like) tumor cells were enriched for MEK activation signatures. Single-cell RNA-sequencing of mouse intracranial glioblastomas treated with the MEK inhibitor selumetinib identified distinct responses among tumor subpopulations. MEK inhibition selectively depleted MES-like cells, and selumetinib-resistant MES-like cells upregulated Ras signaling while resistant non-MES cells expressed markers of glial differentiation. Finally, genome-wide CRISPR interference screens validated Ras/RAF/MEK signaling as a key mediator of selumetinib response. Repression of the RAF regulator SHOC2 sensitized glioblastomas to selumetinib in vitro and in vivo, suggesting a synergistic treatment strategy. Taken together, these results highlighted the heterogeneity of NF1-mutant glioblastomas and informed future combination therapies.

Keywords:  Brain cancer; Drug screens; Genetics; Molecular genetics; Oncology

DOI:  https://doi.org/10.1172/jci.insight.192658
bioRxiv. 2025 Sep 18. pii: 2025.09.15.676412. [Epub ahead of print]

Gliomas phenocopy an inborn error of metabolism to drive neuronal activity and tumor growth.

Kalil G Abdullah, Kenji Miki, Charles K Edgar, Shuangcheng Alivia Wu, Yi Xiao, Milan R Savani, Maged T Ghoche, Shawn E Kotermanski, Yuan-Tai Huang, Jeffrey I Traylor, Lei Guo, Kathryn Gunn, William H Hicks, Diana D Shi, Min Tang, Michael M Levitt, Mohamad El-Shami, Skyler Oken, Namya Manoj, Bailey C Smith, Vinesh T Puliyappadamba, Pranita Kaphle, Tracey Shipman, Raymond E West, Chaoying Liang, Toral R Patel, Kimmo J Hatanpaa, Prithvi Raj, Shang Ma, Alexander Ksendzovsky, Thomas D Nolin, Bradley C Lega, Pascal O Zinn, Bianca J Kuhn, Natalie M Clark, C Williams, D R Mani, Michael A Gillette, Marco A Calzado, Lin Xu, Lauren G Zacharias, Feng Cai, Thomas P Mathews, Julie-Aurore Losman, Timothy E Richardson, Benjamin Levi, Michelle Monje, Jay R Gibson, Osaama H Khan, Sameer Agnihotri, Kimberly M Huber, Simon Chamberland, Ralph J DeBerardinis, Samuel K McBrayer.

The metabolic hallmarks of high-grade glioma (HGG) are not fully understood. Human brain tissue metabolomics revealed that the creatine synthesis pathway intermediate guanidinoacetate (GAA) accumulated ∼100-fold in HGGs relative to controls, which was caused by imbalanced activities of enzymes in this pathway. Glioma cells secreted GAA rather than using it to produce creatine, implicating an unexpected function. GAA accumulates in GAMT deficiency, an inborn error of metabolism, and elevates neuronal excitability. Neuronal excitability is also increased in glioma and drives tumor growth through neuron-glioma interactions. We hypothesized that glioma-generated GAA excites surrounding neurons. Indeed, GAA induced neuronal hyperactivity by activating GABA A receptors and causing depolarizing GABA currents in glioma-associated neurons with dysregulated chloride homeostasis. Depleting tumoral GAA decreased electrochemical activity, neuron-glioma interactions, and tumor aggressiveness. Our findings unveil a new mechanism linking cancer metabolism with cancer neuroscience and leverage human genetics to nominate GAA synthesis as a target in gliomas.

DOI: https://doi.org/10.1101/2025.09.15.676412