bims-malgli 2025-04-27 papers

Issue of 2025–04–27
six papers selected by
Oltea Sampetrean, Keio University

Front Oncol. 2025 ;15 1560008

FGFR3-TACC3 fusion gene promotes glioblastoma malignant progression through the activation of STAT3 signaling pathway.

Yiming Li, Jianshen Liang, Xiude Ren, Jiahe Guo, Xisen Wang, Xuya Wang, Shengping Yu, Tao Li, Xuejun Yang.

Objective: The Fibroblast growth factor receptors 3-transforming acidic coiled-coil-containing protein 3 (FGFR3-TACC3, F3-T3) oncogenic fusion gene, identified in malignant tumors such as gliomas and bladder cancer, has been particularly noted in recurrent gliomas where it is considered to drive malignant progression, thus presenting itself as a viable therapeutic target. However, the precise mechanism by which F3-T3 facilitates the malignant progression of glioma is not fully understood.
Methods: Correction analysis of STAT3 and FGFR3 with major glioma mutation types and pan-cancer analysis was conducted using The Cancer Genome Atlas (TCGA) database. A series of phenotypic experiments, including CCK-8, EdU, colony-formation assay, wound healing assay, and transwell assay were conducted to detect the effects of F3-T3 on proliferation, invasion, and migration of glioma cells. The association between F3-T3 and epithelial-mesenchymal transition (EMT) was investigated through enrichment analysis of the E-MTAB-6037 gene chip database and confirmed by western blot. The underling mechanism were further inferred and validated through RNA sequencing, E-MTAB-6037 gene chip data, and western blot. The relationship between p-STAT3 expression and the WHO grade of glioma was evaluated using immunohistochemistry (IHC) and tissue microarray analysis. Furthermore, the results of vivo experiments and IHC has confirmed the impact of F3-T3 on glioma malignant progression and activation of the STAT3 signaling pathway.
Results: The experimental results from this study indicate that F3-T3 accelerates the epithelial-mesenchymal transition (EMT) process in glioma cells, thereby promoting their proliferation, invasion, and migration capabilities. Mechanistically, it was determined through RNA sequencing that the signal transducer and activator of transcription 3 (STAT3) signaling pathway is crucial for the malignant progression of F3-T3. This finding was further supported through follow-up experiments conducted after STAT3 knockdown. The role of the STAT3 pathway in gliomas was also reinforced through bioinformatic analysis and immunohistochemistry (IHC) on tissue microarrays (TMA). Further in vivo experiments corroborated the role of F3-T3 in enhancing glioma growth and progression.
Conclusion: F3-T3 facilitates the proliferation, invasion, migration and EMT of glioma cells, thereby promoting their malignant progression through STAT3 signaling activation. These findings highlight its potential as a therapeutic target for glioma treatment.

Keywords: FGFR3-TACC3 fusion gene; STAT3 signaling pathway; glioma; invasion; malignant progression; migration

DOI: https://doi.org/10.3389/fonc.2025.1560008

Sci Rep. 2025 Apr 24. 15(1): 14283

Enhanced detection of glioblastoma vasculature with superparamagnetic iron oxide nanoparticles and MRI.

Phillip W Janowicz, Thomas Boele, Richard T Maschmeyer, Yaser H Gholami, Emma G Kempe, Brett W Stringer, Shihani P Stoner, Marie Zhang, Taymin du Toit-Thompson, Fern Williams, Aude Touffu, Lenka Munoz, Zdenka Kuncic, Caterina Brighi, David E J Waddington.

Detecting glioblastoma infiltration in the brain is challenging due to limited MRI contrast beyond the enhancing tumour core. This study aims to investigate the potential of superparamagnetic iron oxide nanoparticles (SPIONs) as contrast agents for improved detection of diffuse brain cancer. We examine the distribution and pharmacokinetics of SPIONs in glioblastoma models with intact and disrupted blood-brain barriers. Using MRI, we imaged RN1-luc and U87MG mice injected with Gadovist and SPIONs, observing differences in blood-brain barrier permeability. Peripheral imaging showed strong uptake of nanoparticles in the liver and spleen, while vascular and renal signals were transient. Susceptibility gradient mapping enabled positive nanoparticle contrast within tumours and provided additional information on tumour angiogenesis. This approach offers a novel method for detecting diffuse brain cancer. Our findings demonstrate that SPIONs enhance glioblastoma detection beyond conventional MRI, providing insights into tumour angiogenesis and opening new avenues for early diagnosis and targeted treatment strategies.

Keywords: Angiogenesis; Biodistribution; Contrast agent; Detection; Diffuse glioblastoma; Ferumoxytol; Glioblastoma; MRI; PEG; PEGylation; SPION; Susceptibility; Susceptibility gradient mapping

DOI: https://doi.org/10.1038/s41598-025-97943-y

Neuro Oncol. 2025 Apr 22. pii: noaf107. [Epub ahead of print]

Therapy-induced senescent glioblastoma cells sustain a procancer immune microenvironment by activating DDX58-mediated STAT1 signaling.

Zhixing Wang, Yuxin Zhang, Fan Wu, Bojun Qiu, Yiyun Yin, Xinrun Wang, Ruoyu Huang, Xin Zhang, Zhiyan Sun, Wanjun Tang, Zefan Jing, Wei Han, Tao Jiang, Xiaozhong Peng.

BACKGROUND: Depending on the context, therapy-induced cancer cell senescence promotes or inhibits tumor progression and recurrence, but the underlying mechanism and effects on the tumor immune microenvironment are poorly understood.
METHODS: Here, we developed senescent glioblastoma cell models in vitro via drug treatment. The protumor function of senescent cells was demonstrated by coinjection of chemotherapy-induced senescent cells with tumorigenic GL261 cells in C57BL/6J male mice. In addition, conditioned medium coculture experiments were used to explore the functions of senescent glioblastoma cells in vitro. Mechanistically, through a CRISPR-Cas9-based screen, we revealed that the RNA-binding protein DDX58 was induced in senescent glioblastoma cells. By combining RNA sequencing and protein mass spectrometry analysis, we observed that STAT1 signaling was activated. Immunoprecipitation experiments were subsequently performed to identify the interaction between DDX58 and STAT1.
RESULTS: We show that glioblastoma cells can enter a senescent state after chemotherapy. In vivo, senescent glioblastoma cells have a tumor-promoting function and reduce survival in male mice. Mechanistically, we found that the RNA-binding protein DDX58 plays an important role in therapy-induced senescent glioblastoma. Inhibition of DDX58 slowed therapy-induced senescence. The activation of DDX58 depends on the accumulation of mitochondrial double-stranded RNA (mtdsRNA) in the cytoplasm via the BAX protein. Moreover, DDX58 promotes the recruitment of tumor-associated macrophages (TAMs) and their M2-like polarization by activating the STAT1-mediated transcription of colony-stimulating factor 1 (CSF1). We also revealed that DDX58 regulates STAT1 at the post-translational level by inhibiting the ubiquitin E3 ligase TRIM21-mediated STAT1 ubiquitination. Compared with temozolomide (TMZ) treatment alone, treatment with fludarabine, which blocks STAT1 signaling, combined with TMZ can more effectively reduce the recruitment of TAMs and delay tumor growth in vivo. Moreover, knockdown of STAT1 enhances the therapeutic effect of TMZ in vivo and prolongs the survival of tumor-bearing male mice.
CONCLUSION: A critical mechanism for the protumor immune microenvironment mediated by therapy-induced senescent glioblastoma cells, the DDX58-STAT1-CSF1 axis, may be a potential therapeutic avenue for alleviating traditional therapy-induced glioblastoma cell senescence.

Keywords: DDX58; Glioblastoma; Immune microenvironment; STAT1; Senescence; TAM

DOI: https://doi.org/10.1093/neuonc/noaf107

Nat Commun. 2025 Apr 24. 16(1): 3874

IDH status dictates oHSV mediated metabolic reprogramming affecting anti-tumor immunity.

Upasana Sahu, Matthew P Mullarkey, Sara A Murphy, Joshua C Anderson, Vasanta Putluri, Abu Hena Mostafa Kamal, Jun Hyoung Park, Tae Jin Lee, Alexander L Ling, Benny A Kaipparettu, Ashok Sharma, Nagireddy Putluri, Pamela L Wenzel, Christopher D Willey, E Antonio Chiocca, James M Markert, Balveen Kaur.

Identification of isocitrate dehydrogenase (IDH) mutations has uncovered the crucial role of metabolism in gliomagenesis. Oncolytic herpes virus (oHSV) initiates direct tumor debulking by tumor lysis and activates anti-tumor immunity, however, little is known about the role of glioma metabolism in determining oHSV efficacy. Here we identify that oHSV rewires central carbon metabolism increasing glucose utilization towards oxidative phosphorylation and shuttling glutamine towards reductive carboxylation in IDH wildtype glioma. The switch in metabolism results in increased lipid synthesis and cellular ROS. PKC induces ACSL4 in oHSV treated cells leading to lipid peroxidation and ferroptosis. Ferroptosis is critical to launch an anti-tumor immune response which is important for viral efficacy. Mutant IDH (IDHR132H) gliomas are incapable of reductive carboxylation and hence ferroptosis. Pharmacological blockade of IDHR132H induces ferroptosis and anti-tumor immunity. This study provides a rationale to use an IDHR132H inhibitor to treat high grade IDH-mutant glioma patients undergoing oHSV treatment.

DOI: https://doi.org/10.1038/s41467-025-58911-2

Cell Rep. 2025 Apr 19. pii: S2211-1247(25)00367-5. [Epub ahead of print]44(5): 115596

Combined inhibition of de novo glutathione and nucleotide biosynthesis is synthetically lethal in glioblastoma.

Suresh Udutha, Céline Taglang, Georgios Batsios, Anne Marie Gillespie, Meryssa Tran, Johanna Ten Hoeve, Thomas G Graeber, Pavithra Viswanath.

Understanding the mechanisms by which oncogenic events alter metabolism will help identify metabolic weaknesses that can be targeted for therapy. Telomerase reverse transcriptase (TERT) is essential for telomere maintenance in most cancers. Here, we show that TERT acts via the transcription factor forkhead box O1 (FOXO1) to upregulate glutamate-cysteine ligase (GCLC), the rate-limiting enzyme for de novo biosynthesis of glutathione (GSH, reduced) in multiple cancer models, including glioblastoma (GBM). Genetic ablation of GCLC or pharmacological inhibition using buthionine sulfoximine (BSO) reduces GSH synthesis from [U-13C]-glutamine in GBMs. However, GCLC inhibition drives de novo pyrimidine nucleotide biosynthesis by upregulating the glutamine-utilizing enzymes glutaminase (GLS) and carbamoyl-phosphate synthetase 2, aspartate transcarbamoylase, and dihydroorotatase (CAD) in an MYC-driven manner. Combining BSO with the glutamine antagonist JHU-083 is synthetically lethal in vitro and in vivo and significantly extends the survival of mice bearing intracranial GBM xenografts. Collectively, our studies advance our understanding of oncogene-induced metabolic vulnerabilities in GBMs.

Keywords: CP: Cancer; CP: Metabolism; TERT; brain tumors; cancer; glioblastoma; glutamine metabolism; glutathione; in vivo stable isotope tracing; metabolic synthetic lethality; metabolomics; nucleotide biosynthesis; telomerase reverse transcriptase

DOI: https://doi.org/10.1016/j.celrep.2025.115596

Neuro Oncol. 2025 Apr 22. pii: noaf106. [Epub ahead of print]

Dual αVβ8 Integrin and PD-1 Blockade Overcomes TGFβ-Mediated B-Cell Suppression to Enhance Anti-Glioma Immunity.

BACKGROUND: Immunotherapy has revolutionized cancer treatment but has yet to be translated into brain tumors. Studies in other solid tumors suggest a central role of B-cell immunity in driving immune checkpoint blockade efficacy. In glioblastoma (GBM), tumor B-cells are driven into a regulatory B-cell state that suppresses immune activation and T-cell function.
METHODS: We used spatially resolved transcriptomics and multiplex immunofluorescence to characterize B-cell neighborhoods within GBM and identify enhanced TGFβ-signaling between myeloid and B cells. We generated conditional knockouts to investigate the effects of TGFβ signaling on B-cell function and survival in vivo. Additionally, we combined TGFβ blockade with PD-1 inhibition to evaluate their combined anti-glioma efficacy.
RESULTS: Our findings reveal that myeloid cells are the primary interactors with B-cells in GBM through the TGFβ pathway. Pharmacological or genetic TGFβ blockade expanded intratumoral B-cells and synergized with PD-1 inhibition to enhance survival (60% tumor eradication in dual-treated mice). Therapeutic efficacy critically depended on B-cells, as their depletion abolished survival benefits. Dual αVβ8/PD-1 blockade reduced B-cell-mediated suppression of CD8⁺ T-cell cytotoxicity and increased plasmablast differentiation, while partial efficacy in RagKO mice implicated ancillary roles for innate immunity.
CONCLUSION: Targeting TGFβ signaling using an anti-αVβ8 blocker can impact anti-tumor immunity through different possible mechanisms, of which we highlight the rescuing of B-cell function through synergy with PD-1 checkpoint blockade therapy. Our work underscores the critical role of intratumoral B-cell immunity in enhancing immunotherapy against brain tumors.

Keywords: B-cells; TGFβ; checkpoint-blockade; glioblastoma; tumor microenvironment

DOI: https://doi.org/10.1093/neuonc/noaf106