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Cancer Cell Aug 2023Radiation therapy (RT) provides therapeutic benefits for patients with glioblastoma (GBM), but inevitably induces poorly understood global changes in GBM and its...
Radiation therapy (RT) provides therapeutic benefits for patients with glioblastoma (GBM), but inevitably induces poorly understood global changes in GBM and its microenvironment (TME) that promote radio-resistance and recurrence. Through a cell surface marker screen, we identified that CD142 (tissue factor or F3) is robustly induced in the senescence-associated β-galactosidase (SA-βGal)-positive GBM cells after irradiation. F3 promotes clonal expansion of irradiated SA-βGal GBM cells and orchestrates oncogenic TME remodeling by activating both tumor-autonomous signaling and extrinsic coagulation pathways. Intratumoral F3 signaling induces a mesenchymal-like cell state transition and elevated chemokine secretion. Simultaneously, F3-mediated focal hypercoagulation states lead to activation of tumor-associated macrophages (TAMs) and extracellular matrix (ECM) remodeling. A newly developed F3-targeting agent potently inhibits the aforementioned oncogenic events and impedes tumor relapse in vivo. These findings support F3 as a critical regulator for therapeutic resistance and oncogenic senescence in GBM, opening potential therapeutic avenues.
Topics: Humans; Glioblastoma; Thromboplastin; Cell Line, Tumor; Neoplasm Recurrence, Local; Signal Transduction; Brain Neoplasms; Tumor Microenvironment
PubMed: 37451272
DOI: 10.1016/j.ccell.2023.06.007 -
Cell Reports. Medicine Nov 2023Glioblastoma (GBM) is a hypoxic and "immune-cold" tumor containing rich stromal signaling molecules and cell populations, such as proteases and immunosuppressive...
Glioblastoma (GBM) is a hypoxic and "immune-cold" tumor containing rich stromal signaling molecules and cell populations, such as proteases and immunosuppressive tumor-associated macrophages (TAMs). Here, we seek to profile and characterize the potential proteases that may contribute to GBM immunosuppression. Legumain (LGMN) emerges as the key protease that is highly enriched in TAMs and transcriptionally upregulated by hypoxia-inducible factor 1-alpha (HIF1α). Functionally, the increased LGMN promotes TAM immunosuppressive polarization via activating the GSK-3β-STAT3 signaling pathway. Inhibition of macrophage HIF1α and LGMN reduces TAM immunosuppressive polarization, impairs tumor progression, enhances CD8 T cell-mediated anti-tumor immunity, and synergizes with anti-PD1 therapy in GBM mouse models. Thus, LGMN is a key molecular switch connecting two GBM hallmarks of hypoxia and immunosuppression, providing an actionable therapeutic intervention for this deadly disease.
Topics: Mice; Animals; Glioblastoma; Peptide Hydrolases; Glycogen Synthase Kinase 3 beta; Immunosuppression Therapy; Hypoxia
PubMed: 37858339
DOI: 10.1016/j.xcrm.2023.101238 -
Radiotherapy and Oncology : Journal of... Jul 2023Target delineation in glioblastoma is still a matter of extensive research and debate. This guideline aims to update the existing joint European consensus on delineation...
BACKGROUND AND PURPOSE
Target delineation in glioblastoma is still a matter of extensive research and debate. This guideline aims to update the existing joint European consensus on delineation of the clinical target volume (CTV) in adult glioblastoma patients.
MATERIAL AND METHODS
The ESTRO Guidelines Committee identified 14 European experts in close interaction with the ESTRO clinical committee and EANO who discussed and analysed the body of evidence concerning contemporary glioblastoma target delineation, then took part in a two-step modified Delphi process to address open questions.
RESULTS
Several key issues were identified and are discussed including i) pre-treatment steps and immobilisation, ii) target delineation and the use of standard and novel imaging techniques, and iii) technical aspects of treatment including planning techniques and fractionation. Based on the EORTC recommendation focusing on the resection cavity and residual enhancing regions on T1-sequences with the addition of a reduced 15 mm margin, special situations are presented with corresponding potential adaptations depending on the specific clinical situation.
CONCLUSIONS
The EORTC consensus recommends a single clinical target volume definition based on postoperative contrast-enhanced T1 abnormalities, using isotropic margins without the need to cone down. A PTV margin based on the individual mask system and IGRT procedures available is advised; this should usually be no greater than 3 mm when using IGRT.
Topics: Adult; Humans; Glioblastoma; Radiotherapy Planning, Computer-Assisted; Dose Fractionation, Radiation
PubMed: 37059335
DOI: 10.1016/j.radonc.2023.109663 -
Cell Reports. Medicine Nov 2023The isocitrate dehydrogenase (IDH) gene is recurrently mutated in adult diffuse gliomas. IDH-mutant gliomas are categorized into oligodendrogliomas and astrocytomas,...
The isocitrate dehydrogenase (IDH) gene is recurrently mutated in adult diffuse gliomas. IDH-mutant gliomas are categorized into oligodendrogliomas and astrocytomas, each with unique pathological features. Here, we use single-nucleus RNA and ATAC sequencing to compare the molecular heterogeneity of these glioma subtypes. In addition to astrocyte-like, oligodendrocyte progenitor-like, and cycling tumor subpopulations, a tumor population enriched for ribosomal genes and translation elongation factors is primarily present in oligodendrogliomas. Longitudinal analysis of astrocytomas indicates that the proportion of tumor subpopulations remains stable in recurrent tumors. Analysis of tumor-associated microglia/macrophages (TAMs) reveals significant differences between oligodendrogliomas, with astrocytomas harboring inflammatory TAMs expressing phosphorylated STAT1, as confirmed by immunohistochemistry. Furthermore, inferred receptor-ligand interactions between tumor subpopulations and TAMs may contribute to TAM state diversity. Overall, our study sheds light on distinct tumor populations, TAM heterogeneity, TAM-tumor interactions in IDH-mutant glioma subtypes, and the relative stability of tumor subpopulations in recurrent astrocytomas.
Topics: Humans; Oligodendroglioma; Brain Neoplasms; Microglia; Mutation; Neoplasm Recurrence, Local; Glioma; Astrocytoma; Isocitrate Dehydrogenase
PubMed: 37883975
DOI: 10.1016/j.xcrm.2023.101249 -
Cancer Cell Aug 2023Glioblastoma progression in its early stages remains poorly understood. Here, we transfer PDGFB and genetic barcodes in mouse brain to initiate gliomagenesis and enable...
Glioblastoma progression in its early stages remains poorly understood. Here, we transfer PDGFB and genetic barcodes in mouse brain to initiate gliomagenesis and enable direct tracing of glioblastoma evolution from its earliest possible stage. Unexpectedly, we observe a high incidence of clonal extinction events and progressive divergence in clonal sizes, even after the acquisition of malignant phenotype. Computational modeling suggests these dynamics result from clonal-based cell-cell competition. Through bulk and single-cell transcriptome analyses, coupled with lineage tracing, we reveal that Myc transcriptional targets have the strongest correlation with clonal size imbalances. Moreover, we show that the downregulation of Myc expression is sufficient to drive competitive dynamics in intracranially transplanted gliomas. Our findings provide insights into glioblastoma evolution that are inaccessible using conventional retrospective approaches, highlighting the potential of combining clonal tracing and transcriptomic analyses in this field.
Topics: Mice; Animals; Glioblastoma; Retrospective Studies; Glioma; Gene Expression Profiling; Phenotype
PubMed: 37541243
DOI: 10.1016/j.ccell.2023.07.001 -
Nature Communications Jul 2023The codependency of cholesterol metabolism sustains the malignant progression of glioblastoma (GBM) and effective therapeutics remain scarce. In orthotopic GBM models in...
The codependency of cholesterol metabolism sustains the malignant progression of glioblastoma (GBM) and effective therapeutics remain scarce. In orthotopic GBM models in male mice, we identify that codependent cholesterol metabolism in tumors induces phagocytic dysfunction in monocyte-derived tumor-associated macrophages (TAMs), resulting in disease progression. Manipulating cholesterol efflux with apolipoprotein A1 (ApoA1), a cholesterol reverse transporter, restores TAM phagocytosis and reactivates TAM-T cell antitumor immunity. Cholesterol metabolomics analysis of in vivo-sorted TAMs further reveals that ApoA1 mediates lipid-related metabolic remodeling and lowers 7-ketocholesterol levels, which directly inhibits tumor necrosis factor signaling in TAMs through mitochondrial translation inhibition. An ApoA1-armed oncolytic adenovirus is also developed, which restores antitumor immunity and elicits long-term tumor-specific immune surveillance. Our findings provide insight into the mechanisms by which cholesterol metabolism impairs antitumor immunity in GBM and offer an immunometabolic approach to target cholesterol disturbances in GBM.
Topics: Male; Mice; Animals; Glioblastoma; Oncolytic Viruses; Tumor-Associated Macrophages; Phagocytosis; Cholesterol; Tumor Microenvironment
PubMed: 37474548
DOI: 10.1038/s41467-023-39683-z -
No Shinkei Geka. Neurological Surgery Sep 2023The 5th edition of the WHO Classification of Central Nervous System Tumours(WHO2021)emphasizes the importance of molecular classification. A significant update was that... (Review)
Review
The 5th edition of the WHO Classification of Central Nervous System Tumours(WHO2021)emphasizes the importance of molecular classification. A significant update was that glioblastoma IDH-mutant from WHO2016 was renamed and classified as astrocytoma IDH-mutant WHO grade 4 in WHO2021. This review describes the current updates to the glioblastoma classification, and discusses the essential knowledge regarding daily practice, especially for young neurosurgeons.
Topics: Humans; Glioblastoma; Astrocytoma; Neurosurgeons
PubMed: 37743333
DOI: 10.11477/mf.1436204823 -
Continuum (Minneapolis, Minn.) Feb 2024This article discusses the diagnostic approach to patients with suspected neoplasms of the spinal cord and reviews the most common primary and metastatic spinal...
OBJECTIVE
This article discusses the diagnostic approach to patients with suspected neoplasms of the spinal cord and reviews the most common primary and metastatic spinal neoplasms and their presentations.
LATEST DEVELOPMENTS
Neoplasms of the spinal cord are rare entities that can involve the spinal cord parenchyma, the dura and leptomeninges, or the extradural space. The most common intramedullary spinal cord neoplasms are primary spinal cord tumors, including ependymomas, pilocytic astrocytomas, and diffuse midline gliomas. The most common primary neoplasms of the spine are intradural extramedullary spinal meningiomas, whereas primary neoplasms of the leptomeninges are rare. Advances in molecular characterization of spinal cord tumors and recent clinical trials of these rare entities are expanding the repertoire of systemic therapy options for primary spinal cord neoplasms. Metastases to the spine most often affect the extradural space. Metastatic epidural spinal cord compression is a neurologic emergency that requires a rapid, multidisciplinary response to preserve neurologic function.
ESSENTIAL POINTS
Neurologists should understand the diagnostic approach to neoplasms of the spinal cord. Knowledge of the most common spinal cord neoplasms will allow for appropriate management and optimal patient care.
Topics: Humans; Spinal Cord Neoplasms; Spinal Neoplasms; Spinal Cord; Astrocytoma; Meningeal Neoplasms
PubMed: 38330474
DOI: 10.1212/CON.0000000000001375 -
No Shinkei Geka. Neurological Surgery Sep 2023In the fifth edition central nervous system tumours volume of the WHO Classification of Tumours series, gliomas, glioneuronal tumors, and neuronal tumors are divided...
In the fifth edition central nervous system tumours volume of the WHO Classification of Tumours series, gliomas, glioneuronal tumors, and neuronal tumors are divided into six groups. The term "circumscribed" is used to refer to a relatively contained growth pattern, as compared to other inherently "diffuse" tumors. Circumscribed astrocytic gliomas include six types: pilocytic astrocytoma, high-grade astrocytoma with piloid features, pleomorphic xanthoastrocytoma, subependymal giant cell astrocytoma, chordoid glioma, and astroblastoma, -altered. The vast majority of circumscribed astrocytic gliomas harbor genetic alterations in the mitogen-activated protein kinase pathway. Here, we review the circumscribed astrocytic gliomas, including etiology, clinical and imaging features, pathology and molecular genetics, treatment, and prognosis. This study will lead to better understanding of these newly classified tumors.
Topics: Humans; Astrocytoma; Brain Neoplasms; Central Nervous System Neoplasms; Glioma; Neoplasms, Neuroepithelial
PubMed: 37743340
DOI: 10.11477/mf.1436204830