bims-malgli Biomed News
on Biology of malignant gliomas
Issue of 2026–10–04
eleven papers selected by
Oltea Sampetrean, Keio University
  1. Glioblastoma treatment gels.
  2. Metabolite ratiomics: Rapid diagnosis and classification of gliomas for intraoperative application during brain surgery.
  3. High-throughput spheroid profiling reveals BMP-driven rewiring of glioma cell death responses.
  4. Activins and BMPs: The yin and yang of diffuse midline gliomas.
  5. Stem cell morphology defines functional heterogeneity and therapeutic vulnerabilities in glioblastoma.
  6. CPT1A-mediated IDO1 succinylation shapes EGFRvIII-driven resistance to tumor electric field therapy in glioblastoma.
  7. NFAM1 organizes a lipid raft-restricted DAPP1-PLCG2 module to drive M2-like GAM polarization via Ca²⁺-NFAT1 signaling in glioma.
  8. Persistent chromatin alterations and gene expression reprogramming follow widespread DNA damage in glioblastoma.
  9. Glioma margins gain a third dimension before surgery ends.
  10. SNP rs2853669 potentially elevates the risk of glioblastoma development and leads to worse prognosis when in cis with mutant TERT promoter in a Japanese cohort.
  11. Genomic alterations and treatment define spatiotemporal patterns of glioblastoma recurrence.
  1. Nat Neurosci. 2026 Oct;29(10): 2381
    Glioblastoma treatment gels.
    Shari Wiseman.
      
    DOI:  https://doi.org/10.1038/s41593-026-02479-7
  2. Proc Natl Acad Sci U S A. 2026 Oct 06. 123(40): e2616216123
    Metabolite ratiomics: Rapid diagnosis and classification of gliomas for intraoperative application during brain surgery.
    Mahdiyeh Shahi, Kenneth Lane Virgin, Loizos Michaelides, Diogo Moniz Garcia, Aleeshba N Basil, Alfredo Quiñones-Hinojosa, R Graham Cooks.
      Gliomas are diffusely infiltrative, requiring accurate and sensitive diagnostic tools during surgical resection. Mutations in isocitrate dehydrogenase enzyme (IDH) alter its normal activity and result in accumulation of a unique oncometabolite, 2-hydroxyglutarate (2HG), in tumor cells. However, IDH-wild-type (IDH-wt) gliomas are more common and typically more aggressive. Here, 86 human brain samples were analyzed by syringe touch spray mass spectrometry to evaluate molecular alterations in gliomas. Tandem mass spectrometry (MS/MS) experiments were performed to minimize isobaric and isomeric interferences, and a ratiometric approach (using only signals for endogenous compounds) was employed to improve reliability of the measurements. Multiple ratios for pairs of metabolite signal intensities were found to differentiate tumor samples from nontumor tissue and they stratified glioma subtypes by IDH mutation status and by tumor grade, with several ratios showing 100% agreement with independent clinical assignments (P < 0.0001, Mann-Whitney U test). Increased carnitine relative abundances were found across all glioma subtypes. Importantly, α-aminoadipate was significantly elevated in grade 4 glioma, which may correlate with increased tumor malignancy. Grade 3 gliomas showed markedly higher 2HG abundance than grade 4 samples. In addition, a selection of ratios showed a linear trend with varying tumor cell percentage. Overall, the multiple metabolic ratio alterations indicate a high degree of heterogeneity among glioma subtypes. Furthermore, there are metabolites that can differentiate glioma from nontumor tissue and this measurement can be made by a simple ratiometric method which has potential to be used intraoperatively for margin assessment without diverging from standard of care.
    Keywords:  ambient ionization mass spectrometry; brain cancer; metabolic hallmarks; metabolomics; touch spray mass spectrometry
    DOI:  https://doi.org/10.1073/pnas.2616216123
  3. bioRxiv. 2026 Sep 13. pii: 2026.09.10.750657. [Epub ahead of print]
    High-throughput spheroid profiling reveals BMP-driven rewiring of glioma cell death responses.
    Weaverly Colleen Lee, Jennifer J Salinas, Aastha Gautam, Dimitri Cadet, Matei A Banu, David A Nathanson, Scott J Dixon.
      The mechanisms regulating glioma cell death are poorly understood. Here, we developed a high-throughput method to study cell death in patient-derived glioblastoma (GBM) and diffuse intrinsic pontine glioma (DIPG) spheroids. Using this method, we systematically profiled how extracellular ligands modulate compound-induced cell death. We find that bone morphogenetic protein 2 (BMP2) and BMP4 potently rewire cell death sensitivity. These ligands suppress killing by standard-of-care DNA alkylating agents and kinase inhibitors by inhibiting cell cycle progression. Simultaneously, BMP2/4 prime spheroids for lipid-dependent necrosis (LiDN), a palmitate-dependent form of non-apoptotic cell death that can be triggered by the clinical drug candidate tegavivint. Activating mutations in the BMP receptor ACVR1, found in ∼25% of DIPG tumors, are sufficient to prime cells for LiDN in the absence of BMP ligand. Together, these findings identify a cell death switch that can be activated in glioma cells by BMP signaling.
    DOI:  https://doi.org/10.64898/2026.09.10.750657
  4. Cell Stem Cell. 2026 Oct 01. pii: S1934-5909(26)00344-9. [Epub ahead of print]33(10): 1573-1574
    Activins and BMPs: The yin and yang of diffuse midline gliomas.
    Kavya Prasad, Oren J Becher.
      Patient-derived models of diffuse midline gliomas (DMGs) remain challenging for interrogating tumor biology and investigating novel therapeutics. Xie et al. develop a robust patient-derived brainstem glioma organoid (BSGO) platform, reveal an Activin B-ACVR2A signaling pathway that promotes DMG growth, and identify a promising triple intrathecal therapy to inhibit it.
    DOI:  https://doi.org/10.1016/j.stem.2026.09.002
  5. Neuro Oncol. 2026 Sep 26. pii: noag235. [Epub ahead of print]
    Stem cell morphology defines functional heterogeneity and therapeutic vulnerabilities in glioblastoma.
    Carlotta Barelli, Matteo Bonfanti, Filippo Mirabella, Dario Ricca, Negin Alizadehmohajer, Roberta Bosotti, Ilaria Bertani, Viktoria Sokolova, Alberto Campione, Giovanni M Sicuri, Clelia Peano, Stefania Faletti, Roberto Stefini, Nereo Kalebic.
       BACKGROUND: Glioblastoma (GBM) is an aggressive brain tumor and an unmet clinical need due to its invasiveness and therapy resistance. These features are driven by glioblastoma stem-like cells (GSLCs), which exhibit remarkable functional heterogeneity. While transcriptional profiling has helped define this heterogeneity, it alone does not fully predict cellular behaviors. Because cell morphology is closely linked to function during neurodevelopment, we asked whether integrating morphological and transcriptomic identities could reveal clinically relevant roles of GSLCs.
    METHODS: We employed CellShape-seq, a customised spatial transcriptomics platform integrating cell morphology with transcriptome and applied it to patient-derived GBM organoids. To link GSLC transcriptome to function, we combined assembloid invasion assays, calcium imaging, pharmacological perturbations and time-lapse microscopy.
    RESULTS: We identified three GSLC morphological classes corresponding to distinct transcriptomic states and functional behaviors: nonpolar cells, which show differentiation and therapy sensitivity; elongated cells, which are blood-vessel associated, invasive and chemoresistant; and multipolar cells, which form intercellular networks conveying therapy resistance. Importantly, morphological state remains stable throughout interphase and is readily inherited from mother to daughter cells. However, under pharmacological stress GSLCs show striking morphological plasticity. Namely, Temozolomide treatment is associated with GSLC elongation and branching, while YAP inhibition and gap-junction blockage result in a reduction of elongated and multipolar GSLCs, respectively. Finally, combined targeting of these morphoclass-specific vulnerabilities reduces viability in patient-derived organoids.
    CONCLUSION: Our findings demonstrate that cell morphology provides critical insights into GSLC behaviors and establish a rationale for putative morphology-informed therapies to overcome resistance and improve outcomes in GBM.
    Keywords:  Cell morphology; Chemoresistance; Glioblastoma stem cell; Organoids; Spatial transcriptomics
    DOI:  https://doi.org/10.1093/neuonc/noag235
  6. Nat Commun. 2026 Sep 23. pii: 10277. [Epub ahead of print]17(1):
    CPT1A-mediated IDO1 succinylation shapes EGFRvIII-driven resistance to tumor electric field therapy in glioblastoma.
    Bowen Feng, Boyan Li, Qinran Zhang, Daiyan Wang, Weiyang Ma, Qingtong Wang, Huize Xia, Rongrong Zhao, Hongyu Zhao, Kailiang Zhang, Shaobo Wang, Xinglong Zhang, Chuanzheng Wang, Leyang Hao, Yanhua Qi, Zijie Gao, Ziwen Pan, Jiawei Qiu, Zhe Han, Junzhi Liu, Fangyong Wang, Gang Li, Hao Xue.
      Tumor Electric Field Therapy (TEFT) disrupts mitosis in glioblastoma (GBM), but responses vary markedly among patients. In a retrospective cohort of TEFT-treated GBM, EGFR variant III (EGFRvIII) alteration is associated with shorter progression-free survival, prompting us to investigate a genotype-linked resistance mechanism. TEFT triggers a broadly shared bioenergetic stress response marked by activation of the AMPK-PPARα-CPT1A axis, whereas EGFRvIII primes IDO1 transcription through NF-κB. CPT1A further stabilizes IDO1 by promoting succinylation at lysine 377 through non-canonical LSTase-related activity, thereby limiting TRIM21-dependent ubiquitination and proteasomal degradation. Accumulated IDO1 increases kynurenine production and activates AhR, which upregulates DCLK1 and ARHGEF2 to preserve spindle organization and microtubule dynamics during electric-field exposure. Thus, EGFRvIII converts a general stress-adaptation pathway into a selective cytoprotective program. Genetic or pharmacological disruption of this pathway restores TEFT sensitivity in established and patient-derived GBM cells, organoids, and orthotopic models. Osimertinib suppresses the EGFRvIII-NF-κB-IDO1 arm and enhances TEFT efficacy, while exploratory clinical cases provide preliminary mechanism-informed support for the combination in recurrent EGFR-driven GBM. These findings define a genotype-field convergence mechanism linking metabolic adaptation to mitotic protection and support prospective evaluation of osimertinib plus TEFT.
    DOI:  https://doi.org/10.1038/s41467-026-77927-w
  7. Neuro Oncol. 2026 Oct 01. pii: noag240. [Epub ahead of print]
    NFAM1 organizes a lipid raft-restricted DAPP1-PLCG2 module to drive M2-like GAM polarization via Ca²⁺-NFAT1 signaling in glioma.
    Yaochuan Zhang, Rongjin Chen, Yifu Song, Yibin Lin, Xu Cao, Guofeng Tian, Xiaodi Han, Lin Zong, Juanhan Yu, Li Zhang, Sheng Han.
       BACKGROUND: Glioma-associated macrophages (GAMs) promote glioma progression, but the membrane-proximal mechanisms sustaining their tumor-supportive states remain poorly defined.
    METHODS: Bulk and single-cell transcriptomic analyses, human glioma specimens, GAM models, and orthotopic glioma models were used to define the expression and function of NFAM1. Lipid-raft fractionation, co-immunoprecipitation, proximity ligation, domain-mutant rescue, IP3 and Ca²⁺ measurements, and NFAT1 nuclear translocation assays delineated its signaling mechanism. Pharmacological, macrophage-depletion/reconstitution, and inducible genetic models evaluated its therapeutic relevance.
    RESULTS: NFAM1 was enriched in monocyte-derived, M2-like GAMs and associated with higher glioma grade, IDH-wild-type status, and poor survival. NFAM1 promoted GAM migration and M2-like polarization, thereby enhancing mesenchymal plasticity of glioma stem cells (GSCs), angiogenesis, and glioma progression. Mechanistically, phosphorylated NFAM1 recruited DAPP1 and PLCG2 through ITAM-SH2-dependent interactions within lipid rafts, organizing a spatially coordinated and functionally ordered signaling module. DAPP1 acted upstream of PLCG2 to promote IP3 production, Ca²⁺ signaling, and NFAT1 nuclear translocation. Madecassoside showed ITAM-dependent cellular target engagement with NFAM1, disrupted this signaling module, suppressed tumor-supportive GAM phenotypes, reduced orthotopic tumor growth, and prolonged survival. Its antitumor activity was markedly diminished after peripheral macrophage depletion or reconstitution with NFAM1-deficient bone marrow-derived macrophages. Moreover, inducible NFAM1 knockdown in reconstituted BMDM-derived GAMs after tumor establishment reduced tumor burden and extended survival.
    CONCLUSIONS: NFAM1 spatially organizes lipid-raft-restricted DAPP1-PLCG2-Ca²⁺-NFAT1 signaling in monocyte-derived GAMs and represents a therapeutically targetable vulnerability in glioma.
    Keywords:  Ca²⁺–NFAT1 Signaling; NFAM1; glioma stem cells; glioma-associated macrophages; lipid raft
    DOI:  https://doi.org/10.1093/neuonc/noag240
  8. Nat Commun. 2026 08 29. pii: 10329. [Epub ahead of print]17(1):
    Persistent chromatin alterations and gene expression reprogramming follow widespread DNA damage in glioblastoma.
    Aram S Modrek, Keerthivasan R Chandradoss, Catherine Do, Ravesanker Ezhilarasan, Theodore Sakellaropoulos, Jerome Karp, Yingwen Ding, Ze-Yan Zhang, Maria L G Quiloan, Melanie Graciani, Giulia Cova, Jennifer E Phillips-Cremins, Erik P Sulman, Jane A Skok.
      DNA damage from routine cellular processes or exogenous insults can have a lasting impact on gene regulation beyond genetic mutations1-5. The prevailing paradigm for the consequences of DNA damage repair revolves around restoration of the original genetic sequence, but long-term changes in chromatin configuration, gene expression and DNA modifications have not been analyzed. We introduce numerous, simultaneous Cas9-mediated DNA double strand breaks (DSBs) at defined locations in human glioblastoma cells and track both non-genetic and genetic alterations over time. Megabase-scale genomic alterations that endured two weeks after the initial damage were detected, involving a shift from transiently increased intra-TAD interactions to persistent long range cis and trans contacts, alterations in gene-expression and associated large structural variations. These findings reveal that widespread DNA damage, such as chemotherapy or radiotherapy, can trigger long-term genetic and non-genetic modifications which alter cellular function and may impact tumor outcome and the emergence of resistant cells.
    DOI:  https://doi.org/10.1038/s41467-026-77331-4
  9. Cell. 2026 Oct 01. pii: S0092-8674(26)01071-8. [Epub ahead of print]189(20): 6209-6211
    Glioma margins gain a third dimension before surgery ends.
    Lingyan Shi.
      In this issue of Cell, Liu et al. introduce ULTRA, which combines rapid tissue clearing, single-channel stimulated Raman scattering microscopy, and AI to generate cell-resolved three-dimensional virtual histology of intact glioma specimens in about 30 minutes-fast enough to expose depth-dependent infiltration before surgery ends.
    DOI:  https://doi.org/10.1016/j.cell.2026.09.002
  10. Neuro Oncol. 2026 Sep 28. pii: noag237. [Epub ahead of print]
    SNP rs2853669 potentially elevates the risk of glioblastoma development and leads to worse prognosis when in cis with mutant TERT promoter in a Japanese cohort.
    Daisuke Kawauchi, Yohei Miyake, Brett Taylor, Joseph Bendik, Shunichiro Miki, Mai Honda-Kitahara, Jill Barnholtz-Sloan, Tomoyuki Nakano, Philip Pham, Raghavendra Vadla, Brandon M Jones, Clark Wang, Sejal Patel, Yoshitaka Narita, Frank Furnari.
       BACKGROUND: Mutations in the telomerase reverse transcriptase (TERT) promoter region (TPM), particularly C228T and C250T, are common in IDH-wildtype glioblastoma (GBM). The single nucleotide polymorphism (SNP) rs2853669, also located in the TERT promoter, may influence telomerase activity, though its clinical relevance in GBM remains unclear. This study examined the allelic configuration between rs2853669 and TPM to elucidate their combined effects on TERT expression and clinical outcome.
    METHODS: Seventy-six TPM-positive GBM tumors from Japanese patients were analyzed by nested PCR, and patients were classified by rs2853669 genotype (T/T, T/C, C/C). In the T/C subgroup, the allelic configuration between the SNP and TPM was determined as cis (same allele) or trans (different alleles). Clinical data, TERT expression, and prognosis were compared among groups.
    RESULTS: Among 76 patients, 37 (48.7%) had T/T, 30 (39.5%) had T/C, and 9 (11.8%) had C/C genotypes. The rs2853669 C allele frequency was higher in GBM than in the general Japanese population (31.6% vs 24.5%, p = 0.047). Among T/C cases, 53.3% showed a cis configuration. Patients carrying the SNP and TPM on the same allele (C/C and T/C cis) had shorter overall survival than those carrying them on different alleles (T/T or T/C trans; 19 vs 25 months, p = 0.048), and TERT expression was also lower in this group (p = 0.038).
    CONCLUSION: The rs2853669 C allele may increase GBM susceptibility and, when in cis with TPM, is associated with reduced TERT expression and poorer prognosis, underscoring its biological and clinical significance in TPM-mutant GBM.
    Keywords:  SNP; TERT; glioblastoma; rs2853669; tumorigenesis
    DOI:  https://doi.org/10.1093/neuonc/noag237
  11. Cancer Discov. 2026 Oct 01.
    Genomic alterations and treatment define spatiotemporal patterns of glioblastoma recurrence.
    Sara Blaabjerg Artzi, Dylan Scott Lykke Harwood, Alessio Locallo, Atul Anand, Casper Carstens Lund, Marc Nihøj Klausen, Matilde Righetti, Susanne Brun Madsen, Julie Jacobsen, Nadine Margaretha Hammouda, Maya Jeje Schuang Lü, Nikolaos Patikas, Jingyi Cao, Sven Nelander, Jonathan Frederik Carlsen, Justin D Lathia, Morten Frödin, Dorte Schou Nørøxe, Ulrik Lassen, William L Hwang, Jane Skjøth-Rasmussen, Martin Hemberg, Joachim Weischenfeldt, Bjarne W Kristensen.
      The surgical margin is the primary site of glioblastoma recurrence, yet its molecular features remain poorly characterized. We performed histology-guided sampling and single-cell spatial transcriptomics of surgical margin and adjacent recurrent tumor regions, with matched primary tumors from 40 patients. The surgical margin constituted a distinct wound-healing microenvironment in the post-treatment setting. We also identified malignant states with pronounced mesenchymal transcriptomic and histological features that were enriched at the surgical margin and defined a "stromal" subtype. Patients who transitioned to this subtype at recurrence were characterized by early TP53 mutation, sustained proliferation during adjuvant temozolomide treatment, and shorter survival. Conversely, patients with TP53-wild-type tumors recurring during temozolomide treatment transitioned toward the mesenchymal subtype, with increased p53 pathway activity and reduced proliferation. Functional validation showed TP53 loss-of-function increased temozolomide resistance in a patient-derived glioblastoma model. Our findings identify distinct glioblastoma recurrence trajectories linked to genomic context, treatment exposure, and clinical outcomes.
    DOI:  https://doi.org/10.1158/2159-8290.CD-25-2302
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