bims-malgli 2025-06-29 papers

bims-malgli

Biomed News

on Biology of malignant gliomas

Issue of 2025–06–29
ten papers selected by
Oltea Sampetrean, Keio University

Inhibiting myosin in glioblastoma.
Brain CD73 modulates interferon signaling to regulate glioblastoma invasion.
Small Extracellular Vesicles from Radioresistant H3K27M-Pediatric Diffuse Midline Glioma Cells Modulate Tumor Phenotypes and Radiation Response.
GLUT1 as a Potential Therapeutic Target in Glioblastoma.
The Role of Viruses in the Glioma Tumor Microenvironment: Immunosuppressors or Primers for Anti-Tumor Immunity?
CAF-derived LRRC15 orchestrates macrophage polarization and limits PD-1 immunotherapy efficacy in glioblastoma.
Deciphering the contributions of fecal microbiota from patients with high-grade glioma to tumor development in a humanized microbiome mouse model of glioma.
Novel fusion superkine, IL-24S/IL-15, enhances immunotherapy of brain cancer.
Differential response of patient-derived primary glioblastoma cells to metabolic and adhesion inhibitors.
Barcoded viral tracing identifies immunosuppressive astrocyte-glioma interactions.

Nat Rev Drug Discov. 2025 Jun 24.

Inhibiting myosin in glioblastoma.

Sarah Crunkhorn.

DOI: https://doi.org/10.1038/d41573-025-00113-y
Neurooncol Adv. 2025 Jan-Dec;7(1):7(1): vdaf080

Brain CD73 modulates interferon signaling to regulate glioblastoma invasion.

Konstantina Kyritsi, Jishi Ye, Eugene Douglass, Rafal Pacholczyk, Nobushige Tsuboi, Yoshihiro Otani, Qin Wang, David H Munn, Balveen Kaur, Bangxing Hong.

   Background: Glioblastoma (GBM) is an aggressive malignant brain-tumor that invades adjacent normal brain tissue. Unlike other solid tumors, GBM is infiltrated by various normal brain cells.
Methods: We analyzed tumor invasion in the murine GSC005 glioma model using both immunodeficient and immunocompetent mice, focusing on the role of host-intrinsic and therapeutic interferon signaling in regulating glioblastoma (GBM) invasion.
Results: In this study, we observed that mouse GBM tumor GSC005 grown in immunodeficient (RAG1-KO, NSG) mice exhibited a more invasive phenotype compared to those in immunocompetent C57BL/6J mice. Immunofluorescence staining revealed the presence of vimentin + and GFAP + cells at the tumor-border interface. Bulk mRNA-seq analysis showed that GSC005 tumors in NSG mice displayed an upregulated mesenchymal signature, characterized by epithelial-to-mesenchymal transition (EMT), and downregulation of type-I and type-II interferon signaling. Our data further suggests that host-intrinsic and therapeutic type-I interferon promotes, while type-II interferon inhibits, the GBM mesenchymal signature. CD73, a key regulator of the EMT process, was found to be upregulated in GSC005 tumors in NSG mice compared to C57BL/6J mice. Mechanistic studies revealed that type-I interferon increases CD73 expression in both tumor and stromal cells, such as tumor-associated astrocytes (mAS), while type-II interferon suppresses CD73 in mAS. Functional assays indicated that CD73 modulates both type-I and type-II interferon signaling-mediated GBM invasion.
Conclusion: These findings suggest that therapies inducing type-I or type-II interferon signaling in GBM may reciprocally regulate CD73-mediated mesenchymal transitions, impacting GBM invasion.

Keywords:  CD73; epithelial-mesenchymal-transition; glioblastoma; interferon

DOI:  https://doi.org/10.1093/noajnl/vdaf080
bioRxiv. 2025 Jun 11. pii: 2025.04.14.648723. [Epub ahead of print]

Small Extracellular Vesicles from Radioresistant H3K27M-Pediatric Diffuse Midline Glioma Cells Modulate Tumor Phenotypes and Radiation Response.

Viral D Oza, Kenan A Flores, Yelena Chernyavskaya, Majd A Al-Hamaly, Caitlyn B Smith, Ronald C Bruntz, Jessica S Blackburn.

Pediatric diffuse midline gliomas with the Histone 3 lysine 27-to-methionine mutation (H3K27M-pDMG) are aggressive brain tumors characterized by intrinsic resistance to radiation therapy, the current standard of care. These tumors exhibit significant intratumoral heterogeneity, with distinct subclonal populations likely contributing to therapy resistance. Emerging evidence suggests that small extracellular vesicles (sEV) mediate oncogenic signaling within glioma stem cell populations, yet their role under radiation-induced stress remains poorly understood. In this study, we characterized sEV uptake dynamics among H3K27M-pDMG tumor cells, identified key sEV surface proteins, and demonstrated that sEVs derived from radioresistant (RR) H3K27M-pDMG cells confer radioprotective effects on radiosensitive tumor cells. Molecular profiling revealed that RR-sEVs carry proteins, microRNAs (miRNAs), and metabolites associated with glycolysis, oxidative phosphorylation, and DNA repair. Upon uptake, RR-sEVs reprogrammed recipient cells by altering gene expression and metabolic pathways, and enhancing DNA repair and survival following radiation exposure. These findings provide insights into the role of sEV-mediated intratumoral communication as a contributor to radiation resistance in H3K27M-pDMG and suggest potential therapeutic strategies to disrupt this process and enhance radiation efficacy.

DOI: https://doi.org/10.1101/2025.04.14.648723
Brain Sci. 2025 May 28. pii: 585. [Epub ahead of print]15(6):

GLUT1 as a Potential Therapeutic Target in Glioblastoma.

Fnu Ruchika, Sanika Suvarnapathaki, Antolin Serrano-Farias, Chetan Bettegowda, Jordina Rincon-Torroella.

  Glioblastoma (GBM) is the most common primary brain tumor in adults, with a median survival of 15-18 months. GBM cells, like all tumors, exhibit a metabolic shift known as the Warburg effect, favoring glycolysis even under normoxic conditions. GLUT1 is a primary glucose transporter in GBM cells and has been found to be overexpressed in these cells. The acidic microenvironment created by glycolysis facilitates immune evasion, therapy resistance, and tumor growth. Overexpression of GLUT1 is driven by hypoxia-inducible factor-1α (HIF-1α), c-Myc, and other pathways which have been correlated with tumor aggressiveness as well as poor prognosis Recent studies have highlighted the therapeutic potential of targeting GLUT1 in GBM. Preclinical research shows that GLUT1 inhibitors, such as WZB117 and BAY-876, effectively impair tumor metabolism, reduce cell viability, and improve survival in vitro and in animal models. GLUT1 expression also serves as a prognostic marker, with elevated levels linked to poor outcomes. This review highlights the importance of GLUT1 in GBM biology as a potential therapeutic target and biomarker.

Keywords:  GLUT1; Warburg effect; glioblastoma; hypoxia

DOI:  https://doi.org/10.3390/brainsci15060585
Cancers (Basel). 2025 Jun 14. pii: 1984. [Epub ahead of print]17(12):

The Role of Viruses in the Glioma Tumor Microenvironment: Immunosuppressors or Primers for Anti-Tumor Immunity?

Anna J Hudson, Jay Chandar, Muhammet Enes Gurses, Thomas Malek, Ashish H Shah.

  The WHO estimates that nearly 10-15% of cancers have a known viral etiology, although this number is likely an underestimate. In glioblastoma (GBM), the most common primary brain malignancy, viral associations have been proposed and investigated without a definitive etiology. Viral-host interactions are known to alter cellular growth and stem cell programming, as well as modulate innate immune signaling. However, in GBM, the multifaceted role of endogenous or exogenous viral expression remains unclear. Here, we provide a review of common viral associations in GBM and discuss how these viruses modulate intrinsic cellular processes to enhance anti-viral immune response or suppress anti-tumor immunity.

Keywords:  CMV; glioblastoma; herpesviruses; immunotherapy; tumor microenvironment; viruses

DOI:  https://doi.org/10.3390/cancers17121984
Neuro Oncol. 2025 Jun 26. pii: noaf157. [Epub ahead of print]

CAF-derived LRRC15 orchestrates macrophage polarization and limits PD-1 immunotherapy efficacy in glioblastoma.

Feifei Luo, Yan Mei, Yanwen Li, Jiahao Yang, Shaoyan Xi, Endong Cao, Cong Shen, Dexiang Zhou, Peng Wang, Dong Zhou, Haiping Cai.

   BACKGROUND: The effectiveness of PD-1/PD-L1 immune checkpoint blockade therapy in glioblastoma (GBM) is limited due to the tumor immunosuppressive microenvironment (TIME). Therefore, strategies of reprogramming TIME to a proinflammatory state offers a promising therapeutic approach.
METHODS: We applied bioinformatics analysis of single-cell RNA sequencing (scRNA-seq) and spatial transcriptomics (stRNA-seq) to identify a significant accumulation of a cancer-associated fibroblasts (CAFs) subcluster with elevated LRRC15 expression in the nonresponders to anti-PD-1 therapy. Molecular mechanism of LRRC15 were functionally validated in vitro and in vivo.
RESULTS: These CAFs subcluster drive the infiltration of macrophages (Mφ) into the tumor microenvironment and promote their polarization toward the M2 phenotype. Deletion of Lrrc15 in CAFs significantly restrained tumor growth and prolonged survival in mouse models. Mechanistically, LRRC15 in CAFs promotes IL8 expression by activating the downstream FAK/SRC/NF-κB pathways, leading to Mφ migration and M2-like polarization. In turn, M2-like Mφs secrete TGF-β, which induces LRRC15 expression in CAFs via SMAD2-dependent transcriptional activation. Targeting CAFs subcluster with elevated LRRC15 expression in combination with anti-PD-1 treatment enhanced antitumor efficacy.
CONCLUSIONS: Our findings suggest that targeting LRRC15 may provide a novel strategy to augment anti-PD-1 therapy and overcome immunotherapy resistance in GBM.

Keywords:  LRRC15; cancer-associated fibroblast; glioblastoma; immunotherapy resistant; tumor-associated macrophage

DOI:  https://doi.org/10.1093/neuonc/noaf157
Neurooncol Adv. 2025 Jan-Dec;7(1):7(1): vdaf085

Deciphering the contributions of fecal microbiota from patients with high-grade glioma to tumor development in a humanized microbiome mouse model of glioma.

Cheng Wang, Yiqi Fan, Lu Zhang, Zhanyi Zhao, Feiyang Luo, Kaijian Sun, Meiqin Zeng, Hao Tian, Meichang Peng, Yunhao Luo, Hailin Zhao, Shuai He, Haitao Sun.

   Background: Recent studies have revealed associations between gut microbiota and glioma. However, the underlying mechanisms remain poorly understood. This study primarily aims to elucidate the impact of altered gut microbiota on tumor progression in glioma-bearing mice.
Methods: Fecal samples were collected from glioma patients and healthy controls to compare the effects of human-derived gut microbiota on glioma development in mice. We also analyzed the associations between these microbiota profiles and plasma metabolites.
Results: Significant differences were observed in both the composition and diversity of the gut microbiota between glioma patients and healthy controls. Mice transplanted with gut microbiota from high-grade glioma patients (HGG-FMT) exhibited accelerated glioma progression compared to those transplanted with microbiota from healthy individuals (HC-FMT). Specifically, Eisenbergiella, Mailhella, and Merdimonas were significantly enriched in HGG-FMT mice, while Limosilactobacillus and Anaerospora increased in HC-FMT mice. Furthermore, Merdimonas showed a positive correlation with sphingosine, sphingosine 1-phosphate, and D-sphingosine in HGG-FMT mice. Conversely, Limosilactobacillus was positively correlated with stearidonic acid and eicosapentaenoic acid in HC-FMT mice.
Conclusions: Our findings demonstrate that gut microbiota from high-grade glioma patients can promote glioma progression in mice, potentially through mechanisms involving sphingosine 1-phosphate. This metabolite may enter the bloodstream and accelerate glioma growth, offering novel insights into glioma pathogenesis and potential treatment options.

Keywords:  Merdimonas; glioma; gut microbiota; metabolite; sphingosine 1-phosphate

DOI:  https://doi.org/10.1093/noajnl/vdaf085
J Immunother Cancer. 2025 Jun 22. pii: e011198. [Epub ahead of print]13(6):

Novel fusion superkine, IL-24S/IL-15, enhances immunotherapy of brain cancer.

Amit Kumar, Praveen Bhoopathi, Padmanabhan Mannangatti, Santanu Maji, Anjan K Pradhan, Esha Madan, Alexander L Klibanov, Rajan Gogna, David D Limbrick, Luni Emdad, Swadesh K Das, Paul B Fisher.

   BACKGROUND: Glioblastoma (GBM) is a rapidly growing, aggressive brain tumor with very poor prognosis without currently effective therapies. The immunosuppressive nature of the tumor microenvironment (TME) in GBM hinders the development of effective tumor-eradicating immunotherapies. This hostile TME can be modulated by administering immune-activating cytokines in combination with agents inducing tumor cell death. To achieve these objectives, we sought to harness the cancer-selective cell death-inducing properties of an enhanced "Superkine" version of melanoma differentiation associated gene-7/interleukin-24, IL-24S, and the immune-activating properties of IL-15 to modulate the TME of GBM to maximize therapeutic outcomes.
METHODS: A fusion "Superkine" (FSK) comprised of IL-24S linked to IL-15 was generated, and antitumor effects were evaluated when transduced by a type 5 adenovirus (Ad.5) in a GBM immunocompetent mouse tumor model. To target the delivery of Ad.5 FSK systemically, we employed an innovative approach of focused ultrasound (FUS) paired with microbubbles (MBs), FUS-DMB (FUS plus double MB), to safely transport the FSK engineered Ad.5 construct into mouse brain to overcome limitations of systemic viral delivery and selectivity of the blood-brain barrier.
RESULTS: The FSK stimulated higher tumor regression and enhanced survival in vivo than the individual "Superkine" or cytokine in GBM cancer models. Apoptosis of GBM cells was induced, as well as increased tumor infiltration of T cells, dendritic cells, macrophages and natural killer (NK) cells. The antitumor-inducing activity of FSK is a consequence of induction of cancer-specific growth suppression and induction of apoptosis (IL-24S) as well as diverse effects on immune cells (IL-15 and IL-24S). Antibody neutralization indicates that a primary immune mediator of anticancer activity of FSK is through recruitment and activation of NK cells. Global cytokine analyses indicated no changes in inflammatory cytokines during therapy, suggesting that this strategy will be safe.
CONCLUSION: In summary, treatment with an FSK, consisting of a fusion of IL-24S to IL-15, promotes GBM cell killing and remodeling of the TME by recruiting and activating immune cells supporting the feasibility of developing safe and effective cancer immunotherapeutic fusion proteins and selective delivery in the brain for the therapy of GBM.

Keywords:  Cytokine; Gene therapy; Immune modulatory; Immunotherapy; Natural killer - NK

DOI:  https://doi.org/10.1136/jitc-2024-011198
Clin Exp Med. 2025 Jun 26. 25(1): 220

Differential response of patient-derived primary glioblastoma cells to metabolic and adhesion inhibitors.

Rasha Rezk, Fikret Basar, John Mediavillo, Rebecca Donaldson, Colin Watts, Kristian Franze, Alexandre J Kabla.

  This study aims to investigate the cellular response of Glioblastoma (GBM) to adhesion and metabolic inhibitors, focusing on cell migration and matrix adhesion properties. GBM is the most common incurable brain tumor. Despite decades of research into GBM's chemical and molecular classification, identifying mechanisms of drug resistance has been challenging. Studies on inhibitors targeting cancer cell migration and proliferation rarely consider the heterogeneous migration properties among cells, which may impact patient responses to treatment. In this work, tissue samples were obtained from spatially distinct locations with different 5-aminolevulinic acid (5-ALA) fluorescent intensities-including strongly fluorescent tumor cores, a weakly fluorescent tumor rim, and non-fluorescent tumor margins. These samples were previously shown to be associated with significantly different motility and adhesion properties. We tested the response of tumor cells to adhesion and metabolic inhibitors using metabolic MTT and Cell Titer Glo viability assays, respectively. We also monitored cell survival using time-lapse microscopy, while culturing them on low-modulus polydimethylsiloxane (representing the stiffness of brain tissue). Metabolic viability assays revealed substantial heterogeneity in drug potency across cells from different regions of the tumor. Highly fluorescent tumor core cells were significantly more resistant to an F0F1 ATP synthase inhibitor (Gboxin), and a FAK inhibitor (GSK2256098), while their proliferation ceased post-treatment in vitro. In contrast, cells derived from non-fluorescent tumor margins exhibited higher potency for the ATP synthase inhibitor (Gboxin), but their proliferation persisted post-treatment. Our study demonstrates a correlation between the adhesive and migration properties of cells and their sensitivity to therapeutics in different regions of the tumor within individual patients and between patients with GBM.

Keywords:  Drug discovery; Glioblastoma; Mechanobiology

DOI:  https://doi.org/10.1007/s10238-025-01736-6
Nature. 2025 Jun 25.

Barcoded viral tracing identifies immunosuppressive astrocyte-glioma interactions.

Brian M Andersen, Camilo Faust Akl, Michael A Wheeler, Zhaorong Li, Martin Diebold, Michael Kilian, Joseph M Rone, Aditya Misra, Jessica E Kenison, Joon-Hyuk Lee, Hong-Gyun Lee, Carolina M Polonio, David Merrell, Jakob H Weiss, Lillie Godinez, Gavin Piester, Tomer Illouz, Jessica J Ye, Arianna Ghia, Jazmin Martinez, Elizabeth N Chung, Lena Srun, Daniel Farrenkopf, Lucas E Flausino, Anton M Schüle, Liliana M Sanmarco, Federico Giovannoni, Luca Fehrenbacher, Marc Charabati, Cristina Gutiérrez-Vázquez, Margaret M Cusick, Prem S Prabhakar, Connor C Bossi, Emily Lapinskas, Roni Nowarski, Gad Getz, Keith L Ligon, Marco Prinz, E Antonio Chiocca, David A Reardon, Francisco J Quintana.

Glioblastoma (GBM) is the most lethal primary brain malignancy1. Immunosuppression in the GBM tumour microenvironment (TME) is an important barrier to immune-targeted therapies, but our understanding of the mechanisms of immune regulation in the GBM TME is limited2. Here we describe a viral barcode interaction-tracing approach3 to analyse TME cell-cell communication in GBM clinical samples and preclinical models at single-cell resolution. We combine it with single-cell and bulk RNA-sequencing analyses, human organotypic GBM cultures, in vivo cell-specific CRISPR-Cas9-driven genetic perturbations as well as human and mouse experimental systems to identify an annexin A1-formyl peptide receptor 1 (ANXA1-FPR1) bidirectional astrocyte-GBM communication pathway that limits tumour-specific immunity. FPR1 inhibits immunogenic necroptosis in tumour cells, and ANXA1 suppresses NF-κB and inflammasome activation in astrocytes. ANXA1 expression in astrocytes and FPR1 expression in cancer cells are associated with poor outcomes in individuals with GBM. The inactivation of astrocyte-glioma ANXA1-FPR1 signalling enhanced dendritic cell, T cell and macrophage responses, increasing infiltration by tumour-specific CD8+ T cells and limiting T cell exhaustion. In summary, we have developed a method to analyse TME cell-cell interactions at single-cell resolution in clinical samples and preclinical models, and used it to identify bidirectional astrocyte-GBM communication through ANXA1-FPR1 as a driver of immune evasion and tumour progression.

DOI: https://doi.org/10.1038/s41586-025-09191-9