bims-malgli Biomed News
on Biology of malignant gliomas
Issue of 2023–07–16
twelve papers selected by
Oltea Sampetrean, Keio University
  1. A Review of Glioblastoma and Other Primary Brain Malignancies.
  2. Targeted glioma therapy makes strides.
  3. A Review of Glioblastoma and Other Primary Brain Malignancies-Reply.
  4. A Syx-RhoA-Dia1 signaling axis regulates cell cycle progression, DNA damage, and therapy resistance in glioblastoma.
  5. Dual role of CXCL8 in maintaining the mesenchymal state of glioblastoma stem cells and M2-like tumor-associated macrophages.
  6. NCAPG promotes the progression of glioblastoma by facilitating PARP1-mediated E2F1 transactivation.
  7. Tissue factor is a critical regulator of radiation therapy-induced glioblastoma remodeling.
  8. Lysine methylation promotes NFAT5 activation and determines temozolomide efficacy in glioblastoma.
  9. Spatial cellular architecture predicts prognosis in glioblastoma.
  10. Protocol for generating in vitro glioma models using human-induced pluripotent- or embryonic-stem-cell-derived cerebral organoids.
  11. Glioblastoma lacking necrosis or vascular proliferations: Different clinical presentation but similar outcome, regardless of histology or isolated TERT promoter mutation.
  12. The role of chromatin remodeler SMARCA4/BRG1 in brain cancers: a potential therapeutic target.
  1. JAMA. 2023 07 11. 330(2): 188-189
    A Review of Glioblastoma and Other Primary Brain Malignancies.
    Alick P Wang.
      
    DOI:  https://doi.org/10.1001/jama.2023.8587
  2. Nat Biotechnol. 2023 Jul;41(7): 884
    Targeted glioma therapy makes strides.
      
    DOI:  https://doi.org/10.1038/s41587-023-01869-7
  3. JAMA. 2023 07 11. 330(2): 189-190
    A Review of Glioblastoma and Other Primary Brain Malignancies-Reply.
    Lauren R Schaff, Ingo K Mellinghoff.
      
    DOI:  https://doi.org/10.1001/jama.2023.8590
  4. JCI Insight. 2023 07 10. pii: e157491. [Epub ahead of print]8(13):
    A Syx-RhoA-Dia1 signaling axis regulates cell cycle progression, DNA damage, and therapy resistance in glioblastoma.
    Wan-Hsin Lin, Ryan W Feathers, Lisa M Cooper, Laura J Lewis-Tuffin, Jiaxiang Chen, Jann N Sarkaria, Panos Z Anastasiadis.
      Glioblastomas (GBM) are aggressive tumors that lack effective treatments. Here, we show that the Rho family guanine nucleotide exchange factor Syx promotes GBM cell growth both in vitro and in orthotopic xenografts derived from patients with GBM. Growth defects upon Syx depletion are attributed to prolonged mitosis, increased DNA damage, G2/M cell cycle arrest, and cell apoptosis, mediated by altered mRNA and protein expression of various cell cycle regulators. These effects are phenocopied by depletion of the Rho downstream effector Dia1 and are due, at least in part, to increased phosphorylation, cytoplasmic retention, and reduced activity of the YAP/TAZ transcriptional coactivators. Furthermore, targeting Syx signaling cooperates with radiation treatment and temozolomide (TMZ) to decrease viability in GBM cells, irrespective of their inherent response to TMZ. The data indicate that a Syx-RhoA-Dia1-YAP/TAZ signaling axis regulates cell cycle progression, DNA damage, and therapy resistance in GBM and argue for its targeting for cancer treatment.
    Keywords:  Brain cancer; Cell cycle; Drug therapy; Oncology
    DOI:  https://doi.org/10.1172/jci.insight.157491
  5. Clin Cancer Res. 2023 Jul 13. pii: CCR-22-3273. [Epub ahead of print]
    Dual role of CXCL8 in maintaining the mesenchymal state of glioblastoma stem cells and M2-like tumor-associated macrophages.
    Wei Yuan, Qian Zhang, Danling Gu, Chenfei Lu, Deobrat Dixit, Ryan C Gimple, Yisu Gao, Jiancheng Gao, Daqi Li, Danyan Shan, Lang Hu, Lu Li, Yangqing Li, Shusheng Ci, Hao You, Linping Yan, Kexin Chen, Ningwei Zhao, Chuanhai Xu, Jianyun Lan, Dong Liu, Junxia Zhang, Zhumei Shi, Qiulian Wu, Kailin Yang, Linjie Zhao, Zhixin Qiu, Deguan Lv, Wei Gao, Hui Yang, Fan Lin, Qianghu Wang, Jianghong Man, Chaojun Li, Weiwei Tao, Sameer Agnihotri, Xu Qian, Stephen C Mack, Nu Zhang, Yongping You, Jeremy N Rich, Guan Sun, Xiuxing Wang.
       PURPOSE: The dynamic interplay between glioblastoma stem cells (GSC) and tumor-associated macrophages (TAM) sculpts the tumor immune microenvironment (TIME) and promotes malignant progression of glioblastoma (GBM). However, the mechanisms underlying this interaction are still incompletely understood. Here, we investigate the role of CXCL8 in the maintenance of the mesenchymal state of glioblastoma stem cell populations and reprogramming the TIME to an immunosuppressive state.
    EXPERIMENTAL DESIGN: We performed an integrative multi-omics analyses of RNA sequencing, GBM mRNA expression datasets, immune signatures, and epigenetic profiling to define the specific genes expressed in the mesenchymal GSC subsets. We then used patient-derived GSCs and xenograft murine model to investigate the mechanisms of tumor-intrinsic and extrinsic factor to maintain the mesenchymal state of GSCs and induce TAM polarization.
    RESULTS: We identified CXCL8 was preferentially expressed and secreted by mesenchymal GSCs and activated PI3K/AKT and NF-κB signaling to maintain GSC proliferation, survival, and self-renewal through a cell-intrinsic mechanism. CXCL8 induced signaling through a CXCR2-JAK2/STAT3 axis in TAMs, which supported an M2-like TAM phenotype through a paracrine, cell-extrinsic pathway. Genetic- and small molecule-based inhibition of these dual complementary signaling cascades in GSCs and TAMs suppressed GBM tumor growth and prolonged survival of orthotopic xenograft-bearing mice.
    CONCLUSIONS: CXCL8 plays critical roles in maintaining the mesenchymal state of GSCs and M2-like TAM polarization in GBM, highlighting an interplay between cell-autonomous and cell-extrinsic mechanisms. Targeting CXCL8 and its downstream effectors may effectively improve GBM treatment.
    DOI:  https://doi.org/10.1158/1078-0432.CCR-22-3273
  6. Neuro Oncol. 2023 Jul 09. pii: noad111. [Epub ahead of print]
    NCAPG promotes the progression of glioblastoma by facilitating PARP1-mediated E2F1 transactivation.
    Jianbing Hou, Pan Huang, Minghao Xu, Hao Wang, Yaqian Shao, Xuelian Weng, Yudong Liu, Hongbo Chang, Li Zhang, Hongjuan Cui.
       BACKGROUND: NCAPG, also known as non-SMC condensin I complex subunit G, is mitosis-related protein widely existed in eukaryotic cells. Increasing evidence has demonstrated that aberrant NCAPG expression was strongly associated with various tumors. However, little is known about the function and mechanism of NCAPG in GBM.
    METHODS: The expression and prognostic value of NCAPG were detected in the clinical databases and tumor samples. The function effects of NCAPG downregulation or overexpression were evaluated in GBM cell proliferation, migration, invasion, and self-renewal in vitro and in tumor growth in vivo. The molecular mechanism of NCAPG was researched.
    RESULTS: We identified that NCAPG was upregulated in GBM and associated with poor prognosis. Loss of NCAPG suppressed the progression of GBM cells in vitro and prolonged survival in mouse models of GBM in vivo. Mechanistically, we revealed that NCAPG positively regulated E2F1 pathway activity. By directly interacting with PARP1, a co-activator of E2F1, and facilitating the PARP1-E2F1 interaction to activate E2F1 target gene expression. Intriguingly, we also discovered that NCAPG functioned as a downstream target of E2F1, which was proved by the ChIP and Dual-Luciferase results. Comprehensive datamining and immunocytochemistry analysis revealed that NCAPG expression was positively associated with the PARP1/E2F1 signaling axis.
    CONCLUSIONS: Our findings indicate that NCAPG promotes GBM progression by facilitating PARP1-mediated E2F1 transactivation, suggesting that NCAPG is a potential target for anticancer therapy.
    Keywords:  E2F1; Glioblastoma (GBM); NCAPG; PARP1; Tumor progression
    DOI:  https://doi.org/10.1093/neuonc/noad111
  7. Cancer Cell. 2023 Jul 11. pii: S1535-6108(23)00217-9. [Epub ahead of print]
    Tissue factor is a critical regulator of radiation therapy-induced glioblastoma remodeling.
    Hye-Min Jeon, Jeong-Yub Kim, Hee Jin Cho, Won Jun Lee, Dayna Nguyen, Sung Soo Kim, Young Taek Oh, Hee-Jin Kim, Chan-Woong Jung, Gonzalo Pinero, Tanvi Joshi, Dolores Hambardzumyan, Takuya Sakaguchi, Christopher G Hubert, Thomas M McIntyre, Howard A Fine, Candece L Gladson, Bingcheng Wang, Benjamin W Purow, Jong Bae Park, Myung Jin Park, Do-Hyun Nam, Jeongwu Lee.
      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.
    Keywords:  glioblastoma; senescence; therapeutic resistance; tissue factor; tumor microenvironment
    DOI:  https://doi.org/10.1016/j.ccell.2023.06.007
  8. Nat Commun. 2023 07 10. 14(1): 4062
    Lysine methylation promotes NFAT5 activation and determines temozolomide efficacy in glioblastoma.
    Yatian Li, Zhenyue Gao, Yuhong Wang, Bo Pang, Binbin Zhang, Ruxin Hu, Yuqing Wang, Chao Liu, Xuebin Zhang, Jingxuan Yang, Mei Mei, Yongzhi Wang, Xuan Zhou, Min Li, Yu Ren.
      Temozolomide (TMZ) therapy offers minimal clinical benefits in patients with glioblastoma multiforme (GBM) with high EGFR activity, underscoring the need for effective combination therapy. Here, we show that tonicity-responsive enhancer binding protein (NFAT5) lysine methylation, is a determinant of TMZ response. Mechanistically, EGFR activation induces phosphorylated EZH2 (Ser21) binding and triggers NFAT5 methylation at K668. Methylation prevents NFAT5 cytoplasm interaction with E3 ligase TRAF6, thus blocks NFAT5 lysosomal degradation and cytosol localization restriction, which was mediated by TRAF6 induced K63-linked ubiquitination, resulting in NFAT5 protein stabilization, nuclear accumulation and activation. Methylated NFAT5 leads to the upregulation of MGMT, a transcriptional target of NFAT5, which is responsible for unfavorable TMZ response. Inhibition of NFAT5 K668 methylation improved TMZ efficacy in orthotopic xenografts and patient-derived xenografts (PDX) models. Notably, NFAT5 K668 methylation levels are elevated in TMZ-refractory specimens and confer poor prognosis. Our findings suggest targeting NFAT5 methylation is a promising therapeutic strategy to improve TMZ response in tumors with EGFR activation.
    DOI:  https://doi.org/10.1038/s41467-023-39845-z
  9. Nat Commun. 2023 07 11. 14(1): 4122
    Spatial cellular architecture predicts prognosis in glioblastoma.
    Yuanning Zheng, Francisco Carrillo-Perez, Marija Pizurica, Dieter Henrik Heiland, Olivier Gevaert.
      Intra-tumoral heterogeneity and cell-state plasticity are key drivers for the therapeutic resistance of glioblastoma. Here, we investigate the association between spatial cellular organization and glioblastoma prognosis. Leveraging single-cell RNA-seq and spatial transcriptomics data, we develop a deep learning model to predict transcriptional subtypes of glioblastoma cells from histology images. Employing this model, we phenotypically analyze 40 million tissue spots from 410 patients and identify consistent associations between tumor architecture and prognosis across two independent cohorts. Patients with poor prognosis exhibit higher proportions of tumor cells expressing a hypoxia-induced transcriptional program. Furthermore, a clustering pattern of astrocyte-like tumor cells is associated with worse prognosis, while dispersion and connection of the astrocytes with other transcriptional subtypes correlate with decreased risk. To validate these results, we develop a separate deep learning model that utilizes histology images to predict prognosis. Applying this model to spatial transcriptomics data reveal survival-associated regional gene expression programs. Overall, our study presents a scalable approach to unravel the transcriptional heterogeneity of glioblastoma and establishes a critical connection between spatial cellular architecture and clinical outcomes.
    DOI:  https://doi.org/10.1038/s41467-023-39933-0
  10. STAR Protoc. 2023 Jul 07. pii: S2666-1667(23)00313-1. [Epub ahead of print]4(3): 102346
    Protocol for generating in vitro glioma models using human-induced pluripotent- or embryonic-stem-cell-derived cerebral organoids.
    Yilin Feng, Honghui Zheng, Jiyuan Tang, Xing Li, Ruilin Tian, Shaohua Ma.
      In glioma modeling, existing organoid protocols lack the ability to replicate glioma cell invasion and interaction with normal brain tissue. Here, we present a protocol for generating in vitro brain disease models using human-induced pluripotent- or embryonic-stem-cell-derived cerebral organoids (COs). We describe steps for forming glioma organoids by co-culturing forebrain organoids with U-87 MG cells. We also detail vibratome sectioning of COs to prevent cell death and enhance contact between U-87 MG cells and cerebral tissues.
    Keywords:  Cancer; Neuroscience; Organoids; Tissue Engineering
    DOI:  https://doi.org/10.1016/j.xpro.2023.102346
  11. Neurooncol Adv. 2023 Jan-Dec;5(1):5(1): vdad075
    Glioblastoma lacking necrosis or vascular proliferations: Different clinical presentation but similar outcome, regardless of histology or isolated TERT promoter mutation.
    Maarten M J Wijnenga, Sybren L N Maas, Vera van Dis, C Mircea S Tesileanu, Johan M Kros, Linda Dirven, Hans M Hazelbag, Hendrikus J Dubbink, Arnaud J P E Vincent, Pim J French, Martin J van den Bent.
      
    DOI:  https://doi.org/10.1093/noajnl/vdad075
  12. Oncogene. 2023 Jul 11.
    The role of chromatin remodeler SMARCA4/BRG1 in brain cancers: a potential therapeutic target.
    Sophie M Navickas, Katherine A Giles, Kate H Brettingham-Moore, Phillippa C Taberlay.
      The chromatin remodeler SMARCA4/BRG1 is a key epigenetic regulator with diverse roles in coordinating the molecular programs that underlie brain tumour development. BRG1 function in brain cancer is largely specific to the tumour type and varies further between tumour subtypes, highlighting its complexity. Altered SMARCA4 expression has been linked to medulloblastoma, low-grade gliomas such as oligodendroglioma, high-grade gliomas such as glioblastoma and atypical/teratoid rhabdoid tumours. SMARCA4 mutations in brain cancer predominantly occur in the crucial catalytic ATPase domain, which is associated with tumour suppressor activity. However, SMARCA4 is opposingly seen to promote tumourigenesis in the absence of mutation and through overexpression in other brain tumours. This review explores the multifaceted interaction between SMARCA4 and various brain cancer types, highlighting its roles in tumour pathogenesis, the pathways it regulates, and the advances that have been made in understanding the functional relevance of mutations. We discuss developments made in targeting SMARCA4 and the potential to translate these to adjuvant therapies able to enhance current methods of brain cancer treatment.
    DOI:  https://doi.org/10.1038/s41388-023-02773-9
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