bims-malgli 2025-06-15 papers

bims-malgli

Biomed News

on Biology of malignant gliomas

Issue of 2025–06–15
ten papers selected by
Oltea Sampetrean, Keio University

Top advances of the year: The status of chimeric antigen receptor T cells in neuro-oncology.
Novel GABAAR antagonists target networked gene hubs at the leading-edge in high-grade gliomas.
A self-directed Trojanbot-enzymatic nanobot in neutrobot for active target therapy of glioblastoma.
Not all CBXs are created equal: A role for the disordered central region of CBX4 in pediatric glioma.
MT-125 inhibits non-muscle myosin IIA and IIB and prolongs survival in glioblastoma.
Loss of LAPTM4A inhibits M2 polarization of tumor-associated macrophages in glioblastoma, promoting immune activation and enhancing anti-PD1 therapy.
The Metabolic Orchestration of Immune Evasion in Glioblastoma: From Molecular Perspectives to Therapeutic Vulnerabilities.
Nuclear cholesterol regulates nuclear size and DNA damage responses in cancer stem cells.
Single Cell Spatial Profiling Identifies Region-Specific Extracellular Matrix Adhesion and Signaling Networks in Glioblastoma.
Solid stress estimations via intraoperative 3D navigation in patients with brain tumors.

Cancer. 2025 Jun 15. 131(12): e35935

Top advances of the year: The status of chimeric antigen receptor T cells in neuro-oncology.

Ravi Medikonda, Matthew A Abikenari, Ethan Schonfeld, Michael Lim.



Keywords:  chimeric antigen receptor (CAR) T cell; diffuse midline glioma; glioblastoma; immunotherapy

DOI:  https://doi.org/10.1002/cncr.35935
Neuro Oncol. 2025 Jun 11. pii: noaf143. [Epub ahead of print]

Novel GABAAR antagonists target networked gene hubs at the leading-edge in high-grade gliomas.

Chloe Shard, Anya C Jones, Anahita Fouladzadeh, Helen M Palethorpe, Abbie Francis, Yasmin Boyle, Rebecca J Ormsby, Brittany Dewdney, Yen Yeow, Ishika Mahajan, Matthew Barker, Irina Kuznetsova, Matthew E Jones, Ashwini Patil, Sara Rezaeiravesh, Zi Ying Ng, Santosh I Poonnoose, Anthony Bosco, Santosh Valvi, Alistair R R Forrest, Terrance G Johns, Guillermo A Gomez, Emily V Fletcher.

   BACKGROUND: Ion channel activity underlying biological processes that drive high-grade gliomas (HGG) is largely unknown. We aimed to determine the networking of ion channel genes and validate their expression within HGG patient tumors, to identify ion channel-targeting drugs that would inhibit tumor-promoting processes.
METHODS: We used weighted gene co-expression network analysis (WGCNA) of RNAseq data to identify ion channel gene hubs in diffuse midline glioma (DMG) and glioblastoma. Using scRNA-seq, spatial transcriptomics, and immunohistochemistry, we characterized the expression of identified hubs within patient tumors, validating their role by testing the efficacy of ion channel inhibitors alone or in combination with radiation and temozolomide on the growth and invasion of patient-derived glioblastoma explant organoids (GBOs).
RESULTS: Network analysis revealed a preserved HGG "neuronal regulation" module, containing the greatest number of ion channels, with its corresponding genes concentrated at the tumor's leading-edge. Hubs within this module included γ-Aminobutyric-acid type A receptor (GABAAR) genes GABRA1 (α1) and GABRG2 (γ2), which immunohistochemically colocalized with GABAergic synaptic markers at the leading-edge. GBOs failed to retain this synaptic architecture but expressed a glioblastoma hub GABRA5 (α5), a component of extrasynaptic GABAARs. S44819, an α5-GABAAR antagonist strongly inhibited GBO invasion, with GABA(A)-compound 1b, a partial antagonist of GABAARs, robustly inhibiting GBO proliferation and invasion. Moreover, combined with standard of care (SOC) regimens, the anti-invasive properties of both compounds were enhanced in GBOs.
CONCLUSIONS: Our co-expression network analysis identified key ion channels at the leading-edge in HGGs, which can be targeted by GABAAR-acting drugs to disrupt tumor progression.

Keywords:  GABAARs; WGCNA; high-grade glioma; leading-edge; synapse

DOI:  https://doi.org/10.1093/neuonc/noaf143
Nat Commun. 2025 Jun 06. 16(1): 5263

A self-directed Trojanbot-enzymatic nanobot in neutrobot for active target therapy of glioblastoma.

Yuanyuan Gao, Meng Mao, Yue Li, Mingjun Xuan, Yingjie Wu, Qiang He.

Chemotherapy is an important treatment for glioblastoma (GBM) and a key component of comprehensive GBM therapy. However, the blood-brain barrier (BBB) and complex tumor microenvironment (TME) restrict the diffusion of drugs, which greatly reduces the chemotherapeutic effect on GBM. Single strategies, such as cell-based nanobots to cross the BBB or enzymatic nanobots propelled by enriched substrates in the TME for deep tumor penetration, remain inadequate to address multiple barriers and achieve precise targeting. Here, we develop a Trojan horse-inspired enzymatic nanobot-in-neutrobot system (Trojanbot) to greatly enhance targeted GBM therapy. Trojanbots traverse the BBB by leveraging positive chemotaxis in response to tumor-derived chemokine gradients, after which the released catalase-driven nanobots (CatNbot) undergo directional movement along the H2O2 gradients in TME, facilitating deep tumor penetration. This multi-stage targeting strategy improves drug delivery efficiency, providing considerable potential as a clinical approach for brain tumor treatment.

DOI: https://doi.org/10.1038/s41467-025-60422-z
Mol Cell. 2025 Jun 05. pii: S1097-2765(25)00455-1. [Epub ahead of print]85(11): 2061-2063

Not all CBXs are created equal: A role for the disordered central region of CBX4 in pediatric glioma.

Jongmin J Kim.

In this issue, Lagan et al.1 apply genome-wide and tiling-scan CRISPR screens to uncover a key role for CBX4 and its central region in promoting the growth of diffuse midline glioma cells bearing the H3K27M mutation.

DOI: https://doi.org/10.1016/j.molcel.2025.05.016
Cell. 2025 Jun 03. pii: S0092-8674(25)00569-0. [Epub ahead of print]

MT-125 inhibits non-muscle myosin IIA and IIB and prolongs survival in glioblastoma.

Rajappa S Kenchappa, Laszlo Radnai, Erica J Young, Natanael Zarco, Li Lin, Athanassios Dovas, Christian T Meyer, Ashley Haddock, Alice Hall, Katalin Toth, Peter Canoll, Naveen K H Nagaiah, Gavin Rumbaugh, Michael D Cameron, Theodore M Kamenecka, Patrick R Griffin, Courtney A Miller, Steven S Rosenfeld.

  Glioblastoma (GBM) is the most lethal of primary brain tumors. Here, we report our studies of MT-125, a small-molecule inhibitor of non-muscle myosin II. MT-125 has high brain penetrance and an excellent safety profile, blocks GBM invasion and cytokinesis, and prolongs survival in murine GBM models. By impairing mitochondrial fission, MT-125 increases redox stress and consequent DNA damage, and it synergizes with radiotherapy. MT-125 also induces oncogene addiction to PDGFR signaling through a mechanism that is driven by redox stress, and it synergizes with FDA-approved PDGFR and mTOR inhibitors in vitro. Consistent with this, we find that combining MT-125 with sunitinib, a PDGFR inhibitor, or paxalisib, a combined phosphatidylinositol 3-kinase (PI3K)/mTOR inhibitor, significantly improves survival in orthotopic GBM models over either drug alone. Our results demonstrate that MT-125 is a first-in-class therapeutic that has strong clinical potential for the treatment of GBM.

Keywords:  cancer; glioblastoma; non-muscle myosin II; oncogenic kinases; reactive oxygen species; small-molecule inhibitor; synergy; targeted therapy; toxicology

DOI:  https://doi.org/10.1016/j.cell.2025.05.019
Commun Biol. 2025 Jun 11. 8(1): 909

Loss of LAPTM4A inhibits M2 polarization of tumor-associated macrophages in glioblastoma, promoting immune activation and enhancing anti-PD1 therapy.

Jin Geng, Bing Liang, Zonghao Zhang, Fengping Shan, Xinxin Zhao, Ye Yuan.

Glioma is a highly aggressive central nervous system tumor with limited treatment options, presenting a significant challenge for effective therapy. Despite advancements, the role of tumor-associated macrophages (TAMs) in glioma remains poorly understood, especially regarding their polarization and its impact on the immune response. This study investigates the effects of Lysosomal-associated protein transmembrane 4 A (LAPTM4A) deficiency on the polarization of TAMs and its role in modulating anti-tumor immunity. Using C57BL/6 male mice, we established an orthotopic glioma model and employed single-cell RNA sequencing, flow cytometry, in vitro co-culture systems, and in vivo anti-PD-1 therapy experiments to explore the functional role of LAPTM4A. We found that LAPTM4A promotes M2 polarization of TAMs, contributing to glioma progression by enhancing cell proliferation and invasion. In contrast, LAPTM4A-deficient glioma models show a shift towards M1 macrophage phenotypes, leading to stronger immune activation and increased sensitivity to anti-PD-1 therapy. These results suggest that targeting LAPTM4A may provide a novel strategy to improve glioma treatment by modulating TAM polarization and enhancing immune responses. This research lays the groundwork for future therapies aimed at reprogramming the tumor microenvironment to combat glioblastoma.

DOI: https://doi.org/10.1038/s42003-025-08147-z
Cancers (Basel). 2025 Jun 04. pii: 1881. [Epub ahead of print]17(11):

The Metabolic Orchestration of Immune Evasion in Glioblastoma: From Molecular Perspectives to Therapeutic Vulnerabilities.

Ravi Medikonda, Matthew Abikenari, Ethan Schonfeld, Michael Lim.

  Glioblastoma (GBM) is a highly aggressive primary brain cancer with dismal prognoses despite current standards of care. Immunotherapy is being explored for GBM, given its promising results in other solid malignancies; however, the results from early clinical studies in GBM are disappointing. It has been discovered that GBM has numerous mechanisms of immune resistance, including the physical blood-brain barrier, high intratumoral and intertumoral heterogeneity, and numerous cellular and molecular components in the tumor microenvironment (TME) that promote immunosuppression. Furthermore, GBM utilizes numerous metabolic pathways to establish a survival advantage in the TME. Recently, it has begun to become evident that these complex metabolic pathways that promote GBM growth and invasion also contribute to tumor immune resistance. Aerobic glycolysis provides tumor cells with ample ATP while depleting key glucose and increasing acidity in the TME. Increased glutamine, tryptophan, and arginine metabolism deprives T cells of these necessary amino acids for proper anti-tumor function. Sphingolipid metabolism promotes an immunosuppressive phenotype in the TME and affects immune cell trafficking. This review will discuss, in detail, the key metabolic pathways relevant to GBM pathophysiology which also modulate host immunosuppression.

Keywords:  arginine depletion; glioblastoma; immune evasion; immunometabolism; sphingolipid pathways; tryptophan metabolism; tumor microenvironment

DOI:  https://doi.org/10.3390/cancers17111881
Neuro Oncol. 2025 Jun 07. pii: noaf110. [Epub ahead of print]

Nuclear cholesterol regulates nuclear size and DNA damage responses in cancer stem cells.

Tingting Duan, Suchet Taori, Shruti Bhargava, Sisi Lai, Cuiqing Zhong, Shira Yomtoubian, Huairui Yuan, Xujia Wu, Po Zhang, Tengfei Huang, Donghai Wang, Fanen Yuan, Daqi Li, Huan Li, Hailong Mi, Weichi Wu, Rui Wang, Ahmed Habib, Farrukh Hammed, Frank P Vendetti, Pascal O Zinn, Christopher J Bakkenist, Marlies Meisel, Qiulian Wu, Jeremy N Rich.

   BACKGROUND: Nuclear atypia is associated with increased malignancy in numerous cancers, including glioblastoma (GBM). Here, we found that GBM stem cells display small nuclear size, prompting investigation of mechanisms underlying nuclear size regulation in the tumor hierarchy.
METHODS: We performed comparative gene expression and proteomics in GBM stem cells (GSCs) and neural stem cells (NSCs) to discover potential regulators of nuclear size. Through transcriptomic analysis, mass spectrometry, and pharmacologic inhibition, we interrogated the functional significance of nuclear size regulation.
RESULTS: GSCs were enriched for a nuclear sterol reductase, Lamin B Receptor (LBR). Targeting LBR increased nuclear size and decreased GSC viability and tumor initiation. Regulation of nuclear cholesterol synthesis underlaid LBR-dependency in GSCs. Loss of LBR or reduction of cholesterol levels induced double-strand DNA breaks (DSBs), activating P53-dependent DNA damage responses (DDR). The GSC proteomic LBR interactome revealed DDR mediators, including DEAD-box RNA helicase DDX5 that resolves R-loops at DSBs. Genetic targeting of LBR reduced the DDX5-R loop interaction, leading to increased R-loop formation rescued by cholesterol supplementation. Pharmacological sterol reductase inhibition mirrored genetic LBR targeting by reducing the DDX5-R loop interaction and increasing R-loops and DSBs. Targeting LBR genetically and pharmacologically inhibits GSC growth in vivo and synergizes with irradiation.
CONCLUSIONS: Stem-like GBM cells display reduced nuclear size, driven by nuclear cholesterol synthesis to regulate radiation responses, revealing a novel therapeutic paradigm.

Keywords:  Cancer stem cell; Lamin B receptor; cholesterol; glioblastoma; radiation

DOI:  https://doi.org/10.1093/neuonc/noaf110
bioRxiv. 2025 Jun 09. pii: 2024.10.31.621280. [Epub ahead of print]

Single Cell Spatial Profiling Identifies Region-Specific Extracellular Matrix Adhesion and Signaling Networks in Glioblastoma.

Arpan De, Santiago A Forero, Ali Pirani, John E Morales, Marisol De La Fuente-Granada, Sumod Sebastian, Jason T Huse, Leomar Y Ballester, Jeffrrey S Weinberg, Frederick F Lang, Kadir C Akdemir, Joseph H McCarty.

The human brain contains a rich milieu of extracellular matrix (ECM) components that are often dysregulated in pathologies including the malignant cancer glioblastoma (GBM). Here, we have used in situ single-cell spatial transcriptomic platforms to map the expression patterns of nearly 400 ECM genes in normal brain and GBM samples. Our analysis identifies at least four different GBM cell populations with unique ECM expression profiles that show spatial enrichment in distinct intratumor regions. Spatial mapping also demonstrates largely non-overlapping expression signatures of various ECM components in GBM stromal cell types, particularly in vascular endothelial cells and reactive microglia/macrophages. Comparisons of GBM (IDH1 wild type) versus lower-grade II and III astrocytoma samples (IDH1 R132H) identifies differential expression of key ECM components, including elevated levels of select ECM glycoproteins (IGFBP2 and MGP) and ECM-affiliated proteins (ANXA1 and ANXA2). In addition, we detect spatially enriched expression of COL8A1 (collagen), LUM (proteoglycan), and POSTN (ECM glycoprotein) in perivascular stromal cells in GBM but not in lower grade tumors. Computational analysis of putative ligand-receptor interactions reveals novel ECM communication networks between cancer cells and stromal components, particularly in regions of GBM microvascular proliferation and pseudopalisading necrosis. In summary, this comprehensive spatial map provides new insights into microenvironmental control of GBM initiation and progression and identifies potential therapeutic targets in the ECM.

DOI: https://doi.org/10.1101/2024.10.31.621280
Clin Cancer Res. 2025 Jun 10.

Solid stress estimations via intraoperative 3D navigation in patients with brain tumors.

Hadi T Nia, Meenal Datta, Ashwin S Kumar, Saeed Siri, Gino B Ferraro, Sampurna Chatterjee, Jeffrey M McHugh, Patrick R Ng, Timothy R West, Otto Rapalino, Bryan D Choi, Brian V Nahed, Lance L Munn, Rakesh K Jain.

PURPOSE: Physical forces exerted by expanding brain tumors - specifically the compressive stresses propagated through solid tissue structures - reduce brain perfusion and neurological function, but heretofore has not been directly measured in patients in vivo. Solid stress levels estimated from tumor growth patterns are negatively correlated with neurological performance in patients. We hypothesize that measurements of solid stress can be used to inform clinical management of brain tumors.
EXPERIMENTAL DESIGN: We developed an intraoperative technique to quantitatively estimate solid stress and brain replacement by the tumor. In 30 patients we made topographic measurements of brain deformation through the craniotomy site with a neuronavigation system during surgical workflows immediately preceding tumor resection (< 5 minutes in the OR). Utilizing these measurements in conjunction with finite element modeling, we calculated solid stress within the tumor and the brain, and estimated the amount of brain tissue replaced, i.e., lost, by the tumor growth.
RESULTS: Mean solid stresses were in the range of 10 to 600 Pa, and the amount of tissue replacement was up to 10% of the brain. Brain loss in patients delineated glioblastoma from brain metastatic tumors, and in mice solid stress was a sensitive biomarker of chemotherapy response.
CONCLUSIONS: We present here a quantitative approach to intraoperatively measure solid stress in patients that can be readily adopted into standard clinical workflows. Brain loss due to tumor growth is a novel mechanical-based biomarker that, in addition to solid stress, may inform personalized management in future clinical studies in brain cancer.

DOI: https://doi.org/10.1158/1078-0432.CCR-24-4159