bims-malgli 2025-03-23 papers

Issue of 2025–03–23
six papers selected by
Oltea Sampetrean, Keio University

Neuro Oncol. 2025 Mar 18. pii: noaf075. [Epub ahead of print]

Dual role of WNT10A in promoting the malignancy of glioblastoma and remodeling the tumor microenvironment.

BACKGROUND: Glioblastoma (GBM) represents a complex ecosystem characterized by numerous interactions between tumor cells and the surrounding tumor microenvironment (TME). Here, we show that WNT10A, a member of the WNT family, plays an important role in GBM growth where its influence is mediated via both autocrine and paracrine pathways thereby stimulating not only the tumor cells but also normal cell types within the tumor microenvironment (TME).
METHODS: In silico analysis was performed to identify high-expressing WNT family members in GBM. Knockdown and overexpression methods were used to examine the function of WNT10A in GBM cells and in orthotopic GBM xenografts in vivo. Co-immunoprecipitation (Co-IP) was used to confirm receptor binding and chromatin immunoprecipitation (ChIP) was performed to analyze transcriptional activation of downstream genes.
RESULTS: WNT10A was found to be highly expressed in GBMs and its knockdown significantly suppressed GBM malignant behavior in vitro and in vivo. Co-IP assays confirmed an interaction between WNT10A and FZD1, which activated the JNK/c-Jun/FOSB signaling pathway and enhanced the transcription of FOSB. Importantly, GBM cells secreted WNT10A into the tumor microenvironment, leading to an activation of the PI3K-AKT pathway in tumor-associated macrophages (TAMs) and the JNK pathway in tumor-associated astrocytes. The latter caused a secretion of tumor-promoting cytokines IL-6, MCP-1, and angiogenin. LGK974, a PORCN inhibitor, inhibited the secretion of WNT10A to suppress the malignant GBM phenotype.
CONCLUSION: Our findings revealed that WNT10A is a critical factor promoting GBM progression through both autocrine and paracrine mechanisms. Thus, our findings provide the foundation for WNT-targeted clinical GBM treatment.

Keywords: Glioblastoma; TAAs; TAMs; WNT10A; microenvironment

DOI: https://doi.org/10.1093/neuonc/noaf075

Immunity. 2025 Mar 13. pii: S1074-7613(25)00089-5. [Epub ahead of print]

Single-cell atlas of endothelial and mural cells across primary and metastatic brain tumors.

Leire Bejarano, Joao Lourenco, Annamaria Kauzlaric, Eleni Lamprou, Catia F Costa, Sabine Galland, Roeltje R Maas, Paola Guerrero Aruffo, Nadine Fournier, Jean-Philippe Brouland, Andreas F Hottinger, Roy T Daniel, Monika E Hegi, Johanna A Joyce.

Central nervous system (CNS) malignancies include primary tumors, such as gliomas, and brain metastases (BrMs) originating from diverse extracranial cancers. The blood-brain barrier (BBB) is a key structural component of both primary and metastatic brain cancers. Here, we comprehensively analyzed the two major BBB cell types, endothelial and mural cells, across non-tumor brain tissue, isocitrate dehydrogenase (IDH) mutant (IDH mut) low-grade gliomas, IDH wild-type (IDH WT) high-grade glioblastomas (GBMs), and BrMs from various primary tumors. Bulk and single-cell RNA sequencing, integrated with spatial analyses, revealed that GBMs, but not low-grade gliomas, exhibit significant alterations in the tumor vasculature, including the emergence of diverse pathological vascular cell subtypes. However, these alterations are less pronounced in GBMs than in BrMs. Notably, the BrM vasculature shows higher permeability and more extensive interactions with distinct immune cell populations. This vascular atlas presents a resource toward understanding of tumor-specific vascular features in the brain, providing a foundation for developing vascular- and immune-targeting therapies.

Keywords: IDH WT glioblastoma; IDH mut glioma; RNA sequencing; brain metastasis; endothelial cells; mural cells; vasculature

DOI: https://doi.org/10.1016/j.immuni.2025.02.022

Acta Neuropathol Commun. 2025 Mar 15. 13(1): 61

Metabolic profiling of adult and pediatric gliomas reveals enriched glucose availability in pediatric gliomas and increased fatty acid oxidation in adult gliomas.

Vladislav O Sviderskiy, Varshini Vasudevaraja, Luiz Gustavo Dubois, James Stafford, Elisa K Liu, Jonathan Serrano, Richard Possemato, Matija Snuderl.

Gliomas are the most common primary brain tumors and a major source of mortality and morbidity in adults and children. Recent genomic studies have identified multiple molecular subtypes; however metabolic characterization of these tumors has thus far been limited. We performed metabolic profiling of 114 adult and pediatric primary gliomas and integrated metabolomic data with transcriptomics and DNA methylation classes. We identified that pediatric tumors have higher levels of glucose and reduced lactate compared to adult tumors regardless of underlying genetics or grade, suggesting differences in availability of glucose and/or utilization of glucose for downstream pathways. Differences in glucose utilization in pediatric gliomas may be facilitated through overexpression of SLC2A4, which encodes the insulin-stimulated glucose transporter GLUT4. Transcriptomic comparison of adult and pediatric tumors suggests that adult tumors may have limited access to glucose and experience more hypoxia, which is supported by enrichment of lactate, 2-hydroxyglutarate (2-HG), even in isocitrate dehydrogenase (IDH) wild-type tumors, and 3-hydroxybutyrate, a ketone body that is produced by oxidation of fatty acids and ketogenic amino acids during periods of glucose scarcity. Our data support adult tumors relying more on fatty acid oxidation, as they have an abundance of acyl carnitines compared to pediatric tumors and have significant enrichment of transcripts needed for oxidative phosphorylation. Our findings suggest striking differences exist in the metabolism of pediatric and adult gliomas, which can provide new insight into metabolic vulnerabilities for therapy.

Keywords: Adult glioma; Fatty acid oxidation; Glucose; H3 mutant; Metabolic profiling; Pediatric glioma

DOI: https://doi.org/10.1186/s40478-025-01961-w

Neuro Oncol. 2025 Mar 20. pii: noaf070. [Epub ahead of print]

Histopathological and molecular characteristics of IDH-wildtype glioblastoma without contrast enhancement: implications for clinical outcomes.

Martha Foltyn-Dumitru, Rouzbeh Banan, Marianne Schell, Mustafa Ahmed Mahmutoglu, Tobias Kessler, Wolfgang Wick, Gianluca Brugnara, Martin Bendszus, Felix Sahm, Philipp Vollmuth.

BACKGROUND: Glioblastoma (GB) heterogeneity poses substantial challenges for diagnosis and treatment. IDH-wildtype GB may lack contrast enhancement on MRI and exhibit a "low-grade radiologic appearance" (non-CE GB), a phenomenon with unclear clinical implications. This study investigates the histopathological and molecular differences and survival outcomes between contrast-enhancing (CE) and non-CE GB.
METHODS: This retrospective study at Heidelberg University Hospital analyzed 457 IDH-wildtype GB cases (09/2009-01/2021). Contrast enhancement on preoperative MRI was volumetrically assessed, classifying tumors as non-CE/CE GB using a 1 cm³ cut-off. Molecular and histopathological features, including microvascular proliferation, necrosis, and overall survival (OS), were compared between the groups.
RESULTS: Of the initial cohort, 352 (77%) patients met the inclusion criteria, with 44 (12.5%) non-CE and 308 (87.5%) CE GB. The histopathological assessment revealed that non-CE GB was less likely to present traditional hallmarks of glioblastoma, such as microvascular proliferation (39% vs. 94%) and necrosis (25% vs. 92%) (p<0.001). In the non-CE group, 24 patients (55%) were diagnosed as molecular-GB, compared to only 8 patients (3%) in the CE group (p < 0.001). A significant difference was observed in Ki-67 levels, with non-CE GBs having a lower mean Ki-67 index of 18 ± 12% compared to 26 ± 13% in CE tumors (p<0.001). The median OS was 27.2 months (95%CI 19.8-NA) for non-CE and 14.7 months (95% CI, 13.2-17.1) for CE GB (p=0.0049).
CONCLUSIONS: IDH-wildtype GBs without contrast enhancement are often diagnosed based on molecular criteria due to less frequent histopathological hallmarks and are associated with prolonged OS.

Keywords: IDH-wildtype glioblastoma; MRI; contrast-enhancement; histopathology; low-grade radiologic appearance

DOI: https://doi.org/10.1093/neuonc/noaf070

Neuron. 2025 Mar 19. pii: S0896-6273(25)00138-2. [Epub ahead of print]113(6): 795-797

Calm in the chaos: Targeting mTOR to reduce glioma-driven neuronal hyperexcitability.

Matthia A Karreman, Varun Venkataramani.

Primary brain tumors induce neuronal hyperexcitability, leading to epileptic seizures. In this issue of Neuron, Goldberg et al.1 demonstrate genetic, structural, and functional alterations to excitatory tumor-associated neurons and how mTOR inhibition rapidly reverses these changes in a mouse model.

DOI: https://doi.org/10.1016/j.neuron.2025.02.020

J Clin Invest. 2025 Mar 17. pii: e183745. [Epub ahead of print]135(6):

Activating antiviral immune responses potentiates immune checkpoint inhibition in glioblastoma models.

Viral mimicry refers to the activation of innate antiviral immune responses due to the induction of endogenous retroelements (REs). Viral mimicry augments antitumor immune responses and sensitizes solid tumors to immunotherapy. Here, we found that targeting what we believe to be a novel, master epigenetic regulator, Zinc Finger Protein 638 (ZNF638), induces viral mimicry in glioblastoma (GBM) preclinical models and potentiates immune checkpoint inhibition (ICI). ZNF638 recruits the HUSH complex, which precipitates repressive H3K9me3 marks on endogenous REs. In GBM, ZNF638 is associated with marked locoregional immunosuppressive transcriptional signatures, reduced endogenous RE expression, and poor immune cell infiltration. Targeting ZNF638 decreased H3K9 trimethylation, increased REs, and activated intracellular dsRNA signaling cascades. Furthermore, ZNF638 knockdown upregulated antiviral immune programs and significantly increased PD-L1 immune checkpoint expression in diverse GBM models. Importantly, targeting ZNF638 sensitized mice to ICI in syngeneic murine orthotopic models through innate IFN signaling. This response was recapitulated in recurrent GBM (rGBM) samples with radiographic responses to checkpoint inhibition with widely increased expression of dsRNA, PD-L1, and perivascular CD8 cell infiltration, suggesting that dsRNA signaling may mediate response to immunotherapy. Finally, low ZNF638 expression was a biomarker of clinical response to ICI and improved survival in patients with rGBM and patients with melanoma. Our findings suggest that ZNF638 could serve as a target to potentiate immunotherapy in gliomas.

Keywords: Brain cancer; Cancer immunotherapy; Epigenetics; Oncology; Virology

DOI: https://doi.org/10.1172/JCI183745