Glioblastoma cell fate is differentially regulated by the microenvironments of the tumor bulk and infiltrative margin

Cell Reports, Journal Year: 2023, Volume and Issue: 42(5), P. 112472 - 112472

Published: May 1, 2023

Glioblastoma (GBM) recurrence originates from invasive margin cells that escape surgical debulking, but to what extent these resemble their bulk counterparts remains unclear. Here, we generated three immunocompetent somatic GBM mouse models, driven by subtype-associated mutations, compare matched and cells. We find that, regardless of tumors converge on common sets neural-like cellular states. However, have distinct biology. Injury-like programs associated with immune infiltration dominate in the bulk, leading generation lowly proliferative injured neural progenitor-like (iNPCs). iNPCs account for a significant proportion dormant are induced interferon signaling within T cell niches. In contrast, developmental-like trajectories favored immune-cold microenvironment resulting differentiation toward astrocyte-like These findings suggest regional tumor dominantly controls fate biological vulnerabilities identified may not extend residuum.

Language: Английский

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Roles of STAT3 in the pathogenesis and treatment of glioblastoma

Frontiers in Cell and Developmental Biology, Journal Year: 2023, Volume and Issue: 11

Published: Feb. 27, 2023

Glioblastoma (GBM) is the most malignant of astrocytomas mainly involving cerebral hemispheres and cortex. It one fatal refractory solid tumors, with a 5-year survival rate merely 5% among adults. IL6/JAK/STAT3 an important signaling pathway involved in pathogenesis progression GBM. The expression STAT3 GBM tissues substantially higher than that normal brain cells. abnormal activation renders tumor microenvironment immunosuppression. Besides, blocking can effectively inhibit growth metastasis On this basis, inhibition may be new therapeutic approach for GBM, combination targeted therapy conventional therapies improve current status treatment. This review summarized roles feasibility target therapy.

Language: Английский

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Histological and molecular glioblastoma, IDH-wildtype: a real-world landscape using the 2021 WHO classification of central nervous system tumors

Frontiers in Oncology, Journal Year: 2023, Volume and Issue: 13

Published: July 6, 2023

Glioblastoma (GBM), the most lethal primary brain malignancy, is divided into histological (hist-GBM) and molecular (mol-GBM) subtypes according to 2021 World Health Organization classification of central nervous system tumors. This study aimed characterize clinical, radiological, molecular, survival features GBM under current scheme explore determinants.We re-examined genetic alterations IDH-wildtype diffuse gliomas at our institute from 2011 2022, enrolled GBMs for analysis after re-classification. Univariable multivariable analyses were used identify determinants.Among 209 gliomas, 191 GBMs, including 146 hist-GBMs (76%) 45 mol-GBMs (24%). Patients with younger, less likely develop preoperative motor dysfunction, more epilepsy than hist-GBMs. Mol-GBMs exhibited lower radiographic incidences contrast enhancement intratumoral necrosis. Common included copy-number changes in chromosomes 1, 7, 9, 10, 19, as well EGFR, TERT, CDKN2A/B, PTEN, distinct patterns observed between two subtypes. The median overall (mOS) GMB was 12.6 months. had a higher mOS hist-GBMs, although not statistically significant (15.6 vs. 11.4 months, p=0.17). Older age, male sex, tumor involvement deep structure or functional area, CDK4, CDK6, CIC, FGFR3, KMT5B, MYB predictors worse prognosis, while MGMT promoter methylation, maximal resection, treatment based on Stupp protocol predictive better survival.The definition its prognostic characteristics have been altered classification.

Language: Английский

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TREM2 is associated with tumor immunity and implies poor prognosis in glioma

Frontiers in Immunology, Journal Year: 2023, Volume and Issue: 13

Published: Jan. 11, 2023

Triggering receptor expressed on myeloid cells 2 (TREM2) is in of the central nervous system (CNS), which mediate immunological response a variety diseases. Uncertain function TREM2 glioma and tumor immune responses. In this research, expression patterns were analyzed, along with its prognostic value functional roles. increased glioblastomas, gliomas mesenchymal subtype, wild-type isocitrate dehydrogenase, without 1p/19q deletion, all suggest aggressiveness poor prognosis gliomas. Gene ontology, KEGG, set variation analyses indicated that may serve as an mediator. However, T against was negatively correlated TREM2, suggesting suppress immunity. Further investigation demonstrated correlation between checkpoint expression. CIBERSORT research revealed link higher level enrichment tumor-associated macrophages, especially M2 subtype. Single-cell analysis multiple immunohistochemical staining results showed microglia macrophage TREM2. Immunofluorescent knocking down would result decrease polarization. discovered to be independent factor glioma. conclusion, our findings significantly intimately associated microenvironment. Thus, it expected small-molecule medications targeting or monoclonal antibodies enhance efficacy immunotherapy.

Language: Английский

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Extracellular LGALS3BP: a potential disease marker and actionable target for antibody–drug conjugate therapy in glioblastoma

Molecular Oncology, Journal Year: 2023, Volume and Issue: 17(8), P. 1460 - 1473

Published: May 17, 2023

Glioblastoma multiforme (GBM) is a lethal disease characterized by an overall survival of about 1 year, making it one the most aggressive tumours, with very limited therapeutic possibilities. Specific biomarkers for early diagnosis as well innovative strategies are urgently needed to improve management this deadly disease. In work, we demonstrated that vesicular galectin-3-binding protein (LGALS3BP), glycosylated overexpressed in variety human malignancies, potential GBM marker and can be efficiently targeted specific antibody-drug conjugate (ADC). Immunohistochemical analysis on patient tissues showed LGALS3BP highly expressed and, compared healthy donors, amount but not total circulating increased. Moreover, plasma-derived extracellular vesicles from mice harbouring revealed used liquid biopsy Finally, ADC targeting LGALS3BP, named 1959-sss/DM4, specifically accumulates tumour tissue, producing potent dose-dependent antitumor activity. conclusion, our work provides evidence novel diagnostic biomarker target deserving further preclinical clinical validation.

Language: Английский

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CircRNF10 triggers a positive feedback loop to facilitate progression of glioblastoma via redeploying the ferroptosis defense in GSCs

Journal of Experimental & Clinical Cancer Research, Journal Year: 2023, Volume and Issue: 42(1)

Published: Sept. 19, 2023

Glioma exhibit heterogeneous susceptibility for targeted ferroptosis. How circRNAs alterations in glioma promote iron metabolism and ferroptosis defense remains unclarified.The highly enriched glioblastoma (GBM) were obtained through analysis of sequencing datasets. Quantitative real-time PCR (qRT-PCR) was used to determine the expression circRNF10 normal brain tissue. Both gain-of-function loss-of-function studies assess effects on using vitro vivo assays. The hypothesis that ZBTB48 promotes established bioinformatics functional RNA pull-down immunoprecipitation (RIP) assays performed examine interaction between target proteins including ZBTB48, MKRN3 IGF2BP3. posttranslational modification mechanism verified coimmunoprecipitation (co-IP) ubiquitination transcription activation HSPB1 IGF2BP3 by confirmed luciferase reporter gene chromatin (ChIP) stabilizing effect explored actinomycin D assay. Finally, a series experiments explore influences progression.A novel circular RNA, hsa_circ_0028912 (named circRNF10), which is significantly upregulated tissues correlated with patients' poor prognosis. Through integrated circRNA-proteins datasets results, we reveal as transcriptional factor binding circRNF10, notably promoting upregulation remodel facilitates launch circRNF10/ZBTB48/IGF2BP3 positive feedback loop GSCs. Additionally, can competitively bind block E3 ubiquitin ligase activity enhance expression. Consequently, circRNF10-overexpressed stem cells (GSCs) display lower Fe2+ accumulation, selectively priming tumors evading.Our research presents abnormal causing molecular metabolic change glioma, leverage discover therapeutically exploitable vulnerability

Language: Английский

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Synergistic Effects of Temozolomide and Doxorubicin in the Treatment of Glioblastoma Multiforme: Enhancing Efficacy through Combination Therapy

Molecules, Journal Year: 2024, Volume and Issue: 29(4), P. 840 - 840

Published: Feb. 14, 2024

Glioblastoma multiforme (GBM), a grade IV (WHO classification) malignant brain tumor, poses significant challenges in treatment. The current standard treatment involves surgical tumor removal followed by radiation and chemotherapeutic interventions. However, despite these efforts, the median survival for GBM patients remains low. Temozolomide, an alkylating agent capable of crossing blood–brain barrier, is currently primary drug Its efficacy, however, limited, leading to exploration combination treatments. In this study, we have investigated synergistic effects combining temozolomide with doxorubicin, widely used against various cancers. Our experiments, conducted on both temozolomide-sensitive (U87) -resistant cells (GBM43 GBM6), demonstrated inhibition cancer Notably, enhanced doxorubicin uptake induced higher apoptosis temozolomide-resistant GBM43 cells. significance our findings lies potential application treatment, even cases resistance. Despite doxorubicin’s inability cross results open avenues alternative delivery methods, such as conjugation carriers like albumin or local administration at site through hydrogel system. study suggests that interaction between holds promise enhancing efficacy glioblastoma positive outcomes observed experiments provide confidence considering strategy benefit glioblastoma.

Language: Английский

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Framework nucleic acid-based nanoparticles enhance temozolomide sensitivity in glioblastoma

Drug Resistance Updates, Journal Year: 2024, Volume and Issue: 76, P. 101122 - 101122

Published: July 27, 2024

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Language: Английский

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Nanoparticles Coated with Brain Microvascular Endothelial Cell Membranes can Target and Cross the Blood–Brain Barrier to Deliver Drugs to Brain Tumors

Small, Journal Year: 2024, Volume and Issue: 20(29)

Published: Feb. 23, 2024

The blood-brain barrier (BBB) contains tightly connected brain microvascular endothelial cells (BMECs) that hinder drug delivery to the brain, which makes tumors difficult treat. Previous studies have shown nanoparticles coated with tumor cell membranes selectively target their homologous tumors. Therefore, this study investigated whether bEnd.3-line BMEC membrane-coated poly(lactide-co-glycolide)-poly(ethylene glycol)-based doxorubicin-loaded cores (BM-PDs) can be used BMECs and cross BBB. In vitro, BM-PDs effectively a BBB model. enter via macropinocytosis, clathrin-mediated endocytosis, caveolin-mediated membrane fusion, result in excellent cellular uptake. also show uptake cells. vivo, BMECs, BBB, accumulate tumors, efficiently kill proposed strategy has great therapeutic potential owing its ability reach

Language: Английский

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Targeted reprogramming of tumor-associated macrophages for overcoming glioblastoma resistance to chemotherapy and immunotherapy

Biomaterials, Journal Year: 2024, Volume and Issue: 311, P. 122708 - 122708

Published: July 20, 2024

Language: Английский

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