bims-malgli Biomed News
on Biology of malignant gliomas
Issue of 2026–01–11
eleven papers selected by
Oltea Sampetrean, Keio University
  1. The source of IDH-mutant gliomas.
  2. BNIP3-mTOR Signaling Mediates Resistance to MET Inhibition in Glioblastoma.
  3. A prognostic matrix gene expression signature defines functional glioblastoma phenotypes and niches.
  4. A cellular epigenetic classification system for glioblastoma.
  5. Necrotic Cells Alter IRE1α-XBP1 Signaling and Induce Transcriptional Changes in Glioblastoma.
  6. Drug and single-cell gene expression integration identifies sensitive and resistant glioblastoma cell populations.
  7. IDH-mutant gliomas arise from glial progenitor cells harboring the initial driver mutation.
  8. Intrathecal CRISPR-edited allogeneic IL-13Rα2 CAR T Cells for recurrent high-grade Glioma: preclinical characterization and phase I trial.
  9. USP10 promotes glioma stem cell maintenance and glioblastoma growth by antagonizing DTX3L-mediated SATB2 ubiquitination.
  10. A Machine Learning-Driven Electrophysiological Platform for Real-Time Tumor-Neural Interaction Analysis and Modulation.
  11. Inhibiting macrophage-derived lactate transport restores cGAS-STING signalling and enhances antitumour immunity in glioblastoma.
  1. Science. 2026 Jan 08. 391(6781): 125-126
    The source of IDH-mutant gliomas.
    Christopher W Mount, Mario L Suvà.
      Deep sequencing of human brain tissue identifies the probable cell of origin of IDH-mutant gliomas.
    DOI:  https://doi.org/10.1126/science.aed6843
  2. bioRxiv. 2025 Dec 29. pii: 2025.12.28.696781. [Epub ahead of print]
    BNIP3-mTOR Signaling Mediates Resistance to MET Inhibition in Glioblastoma.
    Yunzhan Li, Hanif Khan, Seyma Demirsoy, William Bernhardt, Hannah Valensi, Jeongwu Lee, Mitchell Machtay, Dawit Aregawi, Michael Glantz, Pierre Giglio, Shengyu Yang, Todd Schell, Vonn Walter, Yasin Uzun, Inan Olmez.
      Glioblastoma (GBM) is an aggressive primary brain malignancy with poor prognosis due to rapid progression, extensive invasiveness, and intrinsic resistance to standard therapies. Aberrant activation of receptor tyrosine kinases (RTKs), particularly MET, drives tumor proliferation, invasion, and therapy resistance. Here, we show that MET inhibition with crizotinib induces senescence and mitochondrial dysfunction in glioma-initiating cells (GICs), in part via downregulation of the mitochondrial protein BNIP3. However, BNIP3 downregulation activates mTOR signaling, enabling adaptive resistance. Targeting mTOR with everolimus in combination with crizotinib synergistically enhances anti-tumor effects, inducing apoptosis, senescence, and necroptosis, and significantly reducing cell viability and sphere-forming capacity. In orthotopic GBM xenograft models, this combination, particularly in a sequential regimen, markedly prolongs survival without overt toxicity. Our findings identify a BNIP3-mTOR signaling axis as a critical mediator of resistance to MET inhibition and provide a mechanistic rationale for combined MET and mTOR targeting as a promising therapeutic strategy in GBM.
    Statement of Translational Relevance: Glioblastoma (GBM) remains a highly aggressive and treatment-resistant brain tumor with limited therapeutic options. Our study identifies a BNIP3-mTOR signaling axis as a key mediator of resistance to MET inhibition. We show for the first time that combined MET and mTOR inhibition exhibits synergistic effects against GBM in vitro and in vivo. This combination prolongs survival without overt toxicity, providing a strong preclinical rationale for clinical evaluation in GBM patients with high MET expression and offering a promising strategy to overcome adaptive resistance.
    DOI:  https://doi.org/10.64898/2025.12.28.696781
  3. Commun Biol. 2026 Jan 05. 9(1): 18
    A prognostic matrix gene expression signature defines functional glioblastoma phenotypes and niches.
    Monika Vishnoi, Zeynep Dereli, Zheng Yin, Elisabeth K Kong, Meric Kinali, Kisan Thapa, Ozgun Babur, Kyuson Yun, Nourhan Abdelfattah, Xubin Li, Behnaz Bozorgui, Mary C Farach-Carson, Robert C Rostomily, Anil Korkut.
      Interactions among tumor, immune, and vascular niches play major roles in glioblastoma (GBM) malignancy and treatment responses. The composition and heterogeneity of extracellular core matrix proteins (CMPs) that mediate such interactions are not well understood. Here, we present an analysis of the clinical relevance of CMP expression in GBM at bulk, single-cell, and spatial anatomical resolution. We show that CMP enrichment is associated with worse patient survival, specific driver oncogenic alterations, mesenchymal state, pro-tumor immune infiltration, and immune checkpoint expression. Matrisome expression is enriched in vascular and leading edge/infiltrative niches that are known to harbor glioma stem cells. Finally, we identify a 17-gene CMP signature, termed Matrisome 17 (M17), which is a stronger prognostic factor compared to MGMT promoter methylation status as well as canonical subtypes, and importantly, may predict responses to PD1 blockade. Patient stratification based on matrisome profiles can contribute to the selection and optimization of treatment strategies.
    DOI:  https://doi.org/10.1038/s42003-025-09245-8
  4. Neuro Oncol. 2026 Jan 07. pii: noaf299. [Epub ahead of print]
    A cellular epigenetic classification system for glioblastoma.
    Dana Silverbush, Liv Jürgensen, Nelson F Freeburg, Channing S Pooley, Fabio Boniolo, Federico Gaiti, Mario L Suvà, Volker Hovestadt.
       BACKGROUND: Cellular heterogeneity is a defining feature of glioblastoma (GBM), shaping tumor progression and therapeutic response. While single-cell profiling resolves this heterogeneity, it remains impractical for large-cohort studies and clinical implementation. Conversely, DNA methylation-based classification is widely used for GBM diagnostics but does not provide cellular resolution.
    METHODS: We introduce a hierarchical non-negative matrix factorization approach (ITHresolveGBM) to deconvolute bulk DNA methylation profiles, inferring the abundance of glial, immune, and neuronal cells of the microenvironment, and further distinguishing differentiation states of malignant cells.
    RESULTS: Using ITHresolveGBM, we find that low tumor cell content impairs methylation-based classification, most notably linking the mesenchymal subtype with high immune cell infiltration. By integrating multi-omic single-cell data, we show that epigenetic deconvolution captures a malignant differentiation continuum ranging from stem-like to more differentiated tumors. This continuum aligns prior GBM classification systems and is associated with distinct molecular drivers (e.g., PDGFRA, TP53, EGFR) and survival outcomes.
    CONCLUSIONS: Our framework reconciles DNA methylation- and RNA-based classification systems and provides a blueprint for unifying bulk tumor profiles with single-cell biology, thereby refining molecular stratification and enhancing GBM diagnostics.
    Keywords:  Bioinformatics; Cancer; Cellular states; DNA methylation-based classification; Glioblastoma; Single-cell epigenetics
    DOI:  https://doi.org/10.1093/neuonc/noaf299
  5. Int J Mol Sci. 2026 Jan 02. pii: 474. [Epub ahead of print]27(1):
    Necrotic Cells Alter IRE1α-XBP1 Signaling and Induce Transcriptional Changes in Glioblastoma.
    Jiwoo Lim, Seulgi Lee, Ye-Seon Hong, Ji Ha Choi, Ala Jo, Jihee Lee Kang, Tae-Jin Song, Youn-Hee Choi.
      Necrosis is a characteristic feature of glioblastoma multiforme (GBM) and is closely associated with tumor-associated inflammation and poor clinical outcomes. However, the molecular consequences of necrotic cell death on endoplasmic reticulum (ER) stress signaling in GBM cells remain unclear. In this study, we examined the effects of necrotic cells on the ER stress signaling and unfolded protein response (UPR) in human glioblastoma cell lines. Exposure to necrotic cells reduced IRE1α phosphorylation and increased unspliced XBP1 (XBP1u) accumulation, without affecting PERK or ATF6 pathways. These changes were accompanied by enhanced IκBα phosphorylation and impaired autophagic degradation. Treatment with ER stress inducers failed to reverse XBP1u accumulation, and reduced phosphorylation of PKAc was observed together with decreased IRE1α activation. Transcriptomic analysis and quantitative reverse transcription PCR (qRT-PCR) revealed that necrotic cell-induced XBP1u was associated with altered expression of XBP1-related genes, while XBP1 knockdown produced similar transcriptional changes and enhanced the effects of necrotic cell treatment. These findings suggest that necrotic cells impair canonical IRE1α-XBP1 signaling and induce transcriptional reprogramming in glioblastoma cells, which may contribute to tumor progression.
    Keywords:  IRE1α-XBP1 signaling; endoplasmic reticulum stress; glioblastoma; necrosis; unfolded protein response
    DOI:  https://doi.org/10.3390/ijms27010474
  6. Nat Commun. 2026 Jan 07. 17(1): 99
    Drug and single-cell gene expression integration identifies sensitive and resistant glioblastoma cell populations.
    Robert K Suter, Anna M Jermakowicz, Rithvik Veeramachaneni, Matthew D'Antuono, Longwei Zhang, Rishika Chowdary, Simon Kaeppeli, Madison Sharp, Pravallika Palwai, Vasileios Stathias, Grace Baker, Luz Ruiz, Winston Walters, Maria Cepero, Danielle Burgenske, Edward B Reilly, Anatol Oleksijew, Mark G Anderson, Sion Ll Williams, Michael E Ivan, Ricardo J Komotar, Macarena I De La Fuente, Gregory Stein, Alexandre Wojcinski, Santosh Kesari, Jann N Sarkaria, Stephan C Schürer, Nagi G Ayad.
      Glioblastoma (GBM) remains the most common and lethal adult malignant primary brain cancer with few treatment options. A significant issue hindering GBM therapeutic development is intratumor heterogeneity and plasticity. GBM tumors contain neoplastic cells within a fluid spectrum of diverse transcriptional states. Identifying effective therapeutics requires a platform that predicts the differential sensitivity and resistance of these states to various treatments. Here, we develop scFOCAL (Single-Cell Framework for -Omics Connectivity and Analysis via L1000), to quantify the cellular drug sensitivity and resistance landscape. Using single-cell RNA sequencing of newly diagnosed and recurrent GBM tumors, we identify compounds from the LINCS L1000 database with transcriptional response signatures selectively discordant with distinct GBM cell states, and leverage this capability to predict combination synergy. We validate the significance of these findings in vitro, ex vivo, and in vivo, and identify a combination of an OLIG2 inhibitor and Depatux-M for the treatment of GBM. Our studies suggest that scFOCAL identifies cell states that are sensitive and resistant to targeted therapies in GBM using a measure of cell and drug connectivity, which can be applied to identify new synergistic combinations.
    DOI:  https://doi.org/10.1038/s41467-025-67783-5
  7. Science. 2026 Jan 08. 391(6781): eadt0559
    IDH-mutant gliomas arise from glial progenitor cells harboring the initial driver mutation.
    Jung Won Park, Jiehoon Kwak, Keon-Woo Kim, Saehoon Jung, Chang Hyun Nam, Hyun Jung Kim, Sang Mee Lee, Chanho Choi, Yongjin Ahn, Ji-Hyung Park, Jihwan Yoo, Jin-Kyoung Shim, Hye Joung Cho, Eui-Hyun Kim, Chungyeul Kim, Sangjeong Ahn, Stefan Pusch, Andreas von Deimling, Jong Hee Chang, Se Hoon Kim, Hoon Kim, Young Seok Ju, Seok-Gu Kang, Jeong Ho Lee.
      Identifying the cell of origin that harbors an initial driver mutation is key to understanding tumor evolution and for the development of new treatments. For isocitrate dehydrogenase (IDH)-mutant gliomas, the most common malignant primary brain tumor in young adults, the cell of origin is currently poorly understood. We conducted deep sequencing on 142 tissues from 70 individuals comprising tumors, peritumoral cortex or subventricular zones, and blood. Low-level IDH mutations were found in the peritumoral cortex in 37.9% (11 of 29) of patients. Integrating cell-type-specific mutation analysis, the direction of clonal evolution, spatial transcriptomics from patient brains, and a cancer mouse model arising from mutant oligodendrocyte progenitor cell, we determined that glial progenitor cells harboring an initial IDH mutation were responsible for the development of IDH-mutant gliomas.
    DOI:  https://doi.org/10.1126/science.adt0559
  8. Nat Commun. 2026 Jan 06.
    Intrathecal CRISPR-edited allogeneic IL-13Rα2 CAR T Cells for recurrent high-grade Glioma: preclinical characterization and phase I trial.
    Xuetao Li, Xiaoyun Shang, Jiangang Liu, Yang Zhang, Xian Jia, Huabing Li, Yihan Wang, Jianen Gao, Xu Ma, Xuewen Zhang, Xiaoci Rong, Wenjuan Gan, Yu Zhang, Jie Chen, Lin Wang, Zhen Bao, Liang He, Xigang Yan, Yang Liu, Jie Shao, Zongyu Xiao, Zhiming Wang, Haiping Zhu, Zhong Wang, Yuzhang Wu, Yulun Huang.
      Patients with recurrent high-grade glioblastoma have a median survival of 6-8 months, with limited therapeutic options. In recent years, interest has grown in applying chimeric antigen receptor T (CAR-T) cells to solid cancers, including advanced gliomas. Here we generated off-the-shelf CRISPR-Cas9-edited IL-13Rα2-specific allogeneic universal CAR-T cells (MT026) by disrupting the endogenous TCR to prevent graft-versus-host disease and knocking out HLA class I molecules to mitigate the host-versus-graft response, and observed minimal NK-cell-mediated rejection in preclinical studies. In a first-in-human, single-center, open-label investigator-initiated trial (ChiCTR2000028801) in patients with high-grade glioma with prior therapy failure and short life expectancy, intrathecal injection of MT026 via lumbar puncture (1.0-3.0×10^7 cells per dose) demonstrated favorable tolerability and safety (primary outcome), pharmacokinetic characteristics, and preliminary clinical activity (secondary outcomes). Among the five patients enrolled, one achieved a complete response and three achieved partial responses. No grade ≥3 adverse events were observed; the predominant treatment-related toxicities were grade 1-2 pyrexia, hypoxia, and vomiting. Trial enrolment was halted after enrolment of the first five patients, however these preliminary clinical data support the potential benefit of locally administered allogeneic universal CAR-T cell therapy for recurrent glioblastoma.
    DOI:  https://doi.org/10.1038/s41467-025-68112-6
  9. Nat Commun. 2026 Jan 08. 17(1): 164
    USP10 promotes glioma stem cell maintenance and glioblastoma growth by antagonizing DTX3L-mediated SATB2 ubiquitination.
    Mengyue Guo, Wenlong Luo, Peng Ling, Hong Lei, Lihua Li, Chao Duan, Zhen Xue, Min Zhang, Xiaoyan Zhang, Wendai Bao, Wenchao Zhou, Jianghong Man, Suojun Zhang, Kai Shu, Jun Qin, Xiuxing Wang, Zhiqiang Dong, Weiwei Tao.
      Special AT-rich sequence-binding protein 2 (SATB2) is a nuclear matrix-associated protein with a pivotal role in glioblastoma (GBM) progression. However, the mechanisms underpinning aberrant SATB2 expression remain elusive. Here, we identify the ubiquitin specific peptidase 10 (USP10) as a deubiquitinase and the deltex E3 ubiquitin ligase 3 L (DTX3L) as a ubiquitin ligase of SATB2 in glioma stem cells (GSCs). USP10 and DTX3L regulate SATB2 ubiquitination at the K266 residue through mutually exclusive interactions and opposing activities. USP10, enriched in GSCs, is induced by transcription factor YY2. Knockdown of USP10 or overexpression of DTX3L markedly downregulates SATB2, resulting in the inhibition of GSC self-renewal and GBM growth, which can be rescued by the overexpression of SATB2. Importantly, pharmacological inhibition of USP10 by Wu-5 effectively suppresses tumor growth. These findings highlight the antagonistic roles of USP10 and DTX3L in the regulation of GBM malignancy and propose USP10 as a potential therapeutic target.
    DOI:  https://doi.org/10.1038/s41467-025-67418-9
  10. Nat Commun. 2026 Jan 07. 17(1): 49
    A Machine Learning-Driven Electrophysiological Platform for Real-Time Tumor-Neural Interaction Analysis and Modulation.
    Ting Xu, Xinyue Zhang, Youheng Jiang, Kai Sheng, Jie Li, Jinliang Ren, Jiahao He, Chaofeng Liang, Zhenhua Yu, Huawei Jin, Bowen Zhuang, Lujing Li, Ningning Li, Bingzhe Xu.
      Neural-tumor electrophysiology-marked by pathological membrane potentials and ion channel dysregulation-emerges as actionable targets to curb tumor aggression. Yet, how neural-driven bioelectrical crosstalk dynamically regulates tumors within functional circuits remains elusive, demanding tools for real-time interaction decoding. Here, we present a machine learning-driven electrophysiological platform that integrates custom microfluidics with real-time decoding of complex neural-tumor signal dynamics. Our findings show that glioma cells selectively hijack specific subsets of neural signals, reshaping waveform properties and synchronizing their firing events with neural activity. This dynamic interaction plays a critical role in boosting glioma invasiveness, as tumor cells harness neural activity to promote their progression. Notably, targeted stimulation of glioma cells with these hijacked signal patterns-without direct neural involvement-is sufficient to induce hyper-invasive behavior, emphasizing the role of these electrical cues as drivers of tumor aggression.
    DOI:  https://doi.org/10.1038/s41467-025-66988-y
  11. Nat Cell Biol. 2026 Jan 06.
    Inhibiting macrophage-derived lactate transport restores cGAS-STING signalling and enhances antitumour immunity in glioblastoma.
    Daqi Li, Gaoyuan Cui, Kailin Yang, Chenfei Lu, Yuhan Jiang, Le Zhang, Qiulian Wu, Deobrat Dixit, Zhe Zhu, Ryan C Gimple, Danling Gu, Jiancheng Gao, Qiankun Lin, Hang Yu, Zhumei Shi, Yun Chen, Qianghu Wang, Guangfu Jin, Fan Lin, Junfei Shao, Qigang Zhou, Chong Liu, Chaojun Li, Yongping You, Nu Zhang, Junxia Zhang, Xu Qian, Qian Zhang, Jeremy N Rich, Xiuxing Wang.
      Glioblastoma (GBM) is a malignancy with a complex tumour microenvironment (TME) dominated by GBM stem cells (GSCs) and infiltrated by tumour-associated macrophages (TAMs) and exhibits aberrant metabolic pathways. Lactate is a critical glycolytic metabolite that promotes tumour progression; however, the mechanisms of lactate transport and lactylation in the TME of GBM remain elusive. Here we show that lactate is transported from TAMs to GSCs via MCT4-MCT1. TAMs provide lactate to GSCs, promoting GSC proliferation and inducing lactylation of the non-homologous end joining protein KU70 at lysine 317 (K317), which inhibits cGAS-STING signalling and remodels the immunosuppressive TME. Inhibition of lactate transport or targeting the lactylation of KU70, in combination with the immune checkpoint blockade, demonstrates additive therapeutic benefits in immunocompetent xenograft models. This study unveils TAM-derived lactate and lactylation as critical regulators in GSCs to enforce an immunosuppressive microenvironment, opening avenues for developing combinatorial therapy for GBM.
    DOI:  https://doi.org/10.1038/s41556-025-01839-y
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