bims-malgli Biomed News
on Biology of malignant gliomas
Issue of 2023–12–17
eleven papers selected by
Oltea Sampetrean, Keio University
  1. Spatial architecture of high-grade glioma reveals tumor heterogeneity within distinct domains.
  2. Metabolic Modulation of Histone Acetylation Mediated by HMGCL Activates the FOXM1/β-catenin Pathway in Glioblastoma.
  3. Correction: A Compendium of Syngeneic, Transplantable Pediatric High-Grade Glioma Models Reveals Subtype-Specific Therapeutic Vulnerabilities.
  4. Carmofur prevents cell cycle progression by reducing E2F8 transcription in temozolomide-resistant glioblastoma cells.
  5. A new subtype of diffuse midline glioma, H3 K27 and BRAF/FGFR1 co-altered: a clinico-radiological and histomolecular characterisation.
  6. Cholesterol homeostasis confers glioma malignancy triggered by hnRNPA2B1-dependent regulation of SREBP2 and LDLR.
  7. Visualizing Cancer-Originating Acetate Uptake Through MCT1 in Reactive Astrocytes in the Glioblastoma Tumor Microenvironment.
  8. Liquid Biopsy in H3K27M Diffuse Midline Glioma.
  9. Chlorpromazine affects glioblastoma bioenergetics by interfering with pyruvate kinase M2.
  10. Fimepinostat impairs NF-κB and PI3K/AKT signaling and enhances gemcitabine efficacy in H3K27M-mutated diffuse intrinsic pontine glioma.
  11. The potential of amino acid PET imaging for prediction and monitoring of vorasidenib response in IDH-mutant gliomas.
  1. Neurooncol Adv. 2023 Jan-Dec;5(1):5(1): vdad142
    Spatial architecture of high-grade glioma reveals tumor heterogeneity within distinct domains.
    Joel J D Moffet, Oluwaseun E Fatunla, Lutz Freytag, Jurgen Kriel, Jordan J Jones, Samuel J Roberts-Thomson, Anna Pavenko, David K Scoville, Liang Zhang, Yan Liang, Andrew P Morokoff, James R Whittle, Saskia Freytag, Sarah A Best.
       Background: High-grade gliomas (HGGs) are aggressive primary brain cancers with poor response to standard regimens, driven by immense heterogeneity. In isocitrate dehydrogenase (IDH) wild-type HGG (glioblastoma, GBM), increased intratumoral heterogeneity is associated with more aggressive disease.
    Methods: Spatial technologies can dissect complex heterogeneity within the tumor ecosystem by preserving cellular organization in situ. We employed GeoMx digital spatial profiling, CosMx spatial molecular imaging, Xenium in situ mapping and Visium spatial gene expression in experimental and validation patient cohorts to interrogate the transcriptional landscape in HGG.
    Results: Here, we construct a high-resolution molecular map of heterogeneity in GBM and IDH-mutant patient samples to investigate the cellular communities that compose HGG. We uncovered striking diversity in the tumor landscape and degree of spatial heterogeneity within the cellular composition of the tumors. The immune distribution was diverse between samples, however, consistently correlated spatially with distinct tumor cell phenotypes, validated across tumor cohorts. Reconstructing the tumor architecture revealed two distinct niches, one composed of tumor cells that most closely resemble normal glial cells, associated with microglia, and the other niche populated by monocytes and mesenchymal tumor cells.
    Conclusions: This primary study reveals high levels of intratumoral heterogeneity in HGGs, associated with a diverse immune landscape within spatially localized regions.
    Keywords:  brain cancer; glioma; immune microenvironment; sequencing; spatial transcriptomics
    DOI:  https://doi.org/10.1093/noajnl/vdad142
  2. Neuro Oncol. 2023 Dec 09. pii: noad232. [Epub ahead of print]
    Metabolic Modulation of Histone Acetylation Mediated by HMGCL Activates the FOXM1/β-catenin Pathway in Glioblastoma.
    Yanfei Sun, Guangjing Mu, Xuehai Zhang, Yibo Wu, Shuai Wang, Xu Wang, Zhiwei Xue, Chuanwei Wang, Jilong Liu, Wenbo Li, Lin Zhang, Yunyun Guo, Feihu Zhao, Xuemeng Liu, Zhiyi Xue, Yan Zhang, Shilei Ni, Jian Wang, Xingang Li, Mingzhi Han, Bin Huang.
       BACKGROUND: Altered branched-chain amino acid (BCAA) metabolism modulates epigenetic modification, such as H3K27ac in cancer, thus providing a link between metabolic reprogramming and epigenetic change, which are prominent hallmarks of glioblastoma multiforme (GBM). Here, we identified mitochondrial 3-hydroxymethyl-3-methylglutaryl-CoA lyase (HMGCL), an enzyme involved in leucine degradation, promoting GBM progression and glioma stem cell (GSC) maintenance.
    METHODS: In silico analysis was performed to identify specific molecules involved in multiple processes. GBM cells were infected with knockdown/overexpression lentiviral constructs of HMGCL to assess malignant performance in vitro and in an orthotopic xenograft model. RNA sequencing was used to identify potential downstream molecular targets.
    RESULTS: HMGCL as a gene increased in GBM and associated with poor survival in patients. Knockdown of HMGCL suppressed proliferation and invasion in vitro and in vivo. Acetyl-CoA was decreased with HMGCL knockdown, which led to reduced NFAT1 nuclear accumulation and H3K27ac level. RNA sequencing-based transcriptomic profiling revealed FOXM1 as a candidate downstream target, and HMGCL-mediated H3K27ac modification in the FOXM1 promoter induced transcription of the gene. Loss of FOXM1 protein with HMGCL knockdown led to decreased nuclear translocation and thus activity of β-catenin, a known oncogene. Finally, JIB-04, a small molecule confirmed to bind to HMGCL, suppressed GBM tumorigenesis in vitro and in vivo.
    CONCLUSIONS: Changes in acetyl-CoA levels induced by HMGCL altered H3K27ac modification, which triggers transcription of FOXM1 and β-catenin nuclear translocation. Targeting HMGCL by JIB-04 inhibited tumor growth, indicating that mediators of BCAA metabolism may serve as molecular targets for effective GBM treatment.
    Keywords:  FOXM1; Glioblastoma; HMGCL; histone acetylation; metabolic regulation
    DOI:  https://doi.org/10.1093/neuonc/noad232
  3. Cancer Discov. 2023 Dec 12. 13(12): 2674
    Correction: A Compendium of Syngeneic, Transplantable Pediatric High-Grade Glioma Models Reveals Subtype-Specific Therapeutic Vulnerabilities.
      
    DOI:  https://doi.org/10.1158/2159-8290.CD-23-1292
  4. Cell Death Discov. 2023 Dec 12. 9(1): 451
    Carmofur prevents cell cycle progression by reducing E2F8 transcription in temozolomide-resistant glioblastoma cells.
    Cyntanna C Hawkins, Amber B Jones, Emily R Gordon, Yuvika Harsh, Julia K Ziebro, Christopher D Willey, Corinne Griguer, David K Crossman, Sara J Cooper, Sasanka Ramanadham, Ninh Doan, Anita B Hjelmeland.
      Sphingolipid metabolism is dysregulated in many cancers, allowing cells to evade apoptosis through increased sphingosine-1-phosphate (S1P) and decreased ceramides. Ceramidases hydrolyze ceramides to sphingosine, which is phosphorylated by sphingosine kinases to generate S1P. The S1P allows cells to evade apoptosis by shifting the equilibrium away from ceramides, which favor cell death. One tumor type that exhibits a shift in the sphingolipid balance towards S1P is glioblastoma (GBM), a highly aggressive brain tumor. GBMs almost always recur despite surgical resection, radiotherapy, and chemotherapy with temozolomide (TMZ). Understanding sphingolipid metabolism in GBM is still limited, and currently, there are no approved treatments to target dysregulation of sphingolipid metabolism in GBM. Carmofur, a derivative of 5-fluorouracil, inhibits acid ceramidase (ASAH1), a key enzyme in the production of S1P, and is in use outside the USA to treat colorectal cancer. We find that the mRNA for ASAH1, but not other ceramidases, is elevated in recurrent GBM. When TMZ-resistant GBM cells were treated with carmofur, decreased cell growth and increased apoptosis were observed along with cell cycle perturbations. RNA-sequencing identified decreases in cell cycle control pathways that were specific to TMZ-resistant cells. Furthermore, the transcription factor and G1 to S phase regulator, E2F8, was upregulated in TMZ-resistant versus parental GBM cells and inhibited by carmofur treatment in TMZ-resistant GBM cells, specifically. These data suggest a possible role for E2F8 as a mediator of carmofur effects in the context of TMZ resistance. These data suggest the potential utility of normalizing the sphingolipid balance in the context of recurrent GBM.
    DOI:  https://doi.org/10.1038/s41420-023-01738-x
  5. Acta Neuropathol. 2023 Dec 08. 147(1): 2
    A new subtype of diffuse midline glioma, H3 K27 and BRAF/FGFR1 co-altered: a clinico-radiological and histomolecular characterisation.
    Lucie Auffret, Yassine Ajlil, Arnault Tauziède-Espariat, Thomas Kergrohen, Chloé Puiseux, Laurent Riffaud, Pascale Blouin, Anne-Isabelle Bertozzi, Pierre Leblond, Klas Blomgren, Sébastien Froelich, Alberto Picca, Mehdi Touat, Marc Sanson, Kévin Beccaria, Thomas Blauwblomme, Volodia Dangouloff-Ros, Nathalie Boddaert, Pascale Varlet, Marie-Anne Debily, Jacques Grill, David Castel.
      Diffuse midline gliomas (DMG) H3 K27-altered are incurable grade 4 gliomas and represent a major challenge in neuro-oncology. This tumour type is now classified in four subtypes by the 2021 edition of the WHO Classification of the Central Nervous System (CNS) tumours. However, the H3.3-K27M subgroup still appears clinically and molecularly heterogeneous. Recent publications reported that rare patients presenting a co-occurrence of H3.3K27M with BRAF or FGFR1 alterations tended to have a better prognosis. To better study the role of these co-driver alterations, we assembled a large paediatric and adult cohort of 29 tumours H3K27-altered with co-occurring activating mutation in BRAF or FGFR1 as well as 31 previous cases from the literature. We performed a comprehensive histological, radiological, genomic, transcriptomic and DNA methylation analysis. Interestingly, unsupervised t-distributed Stochastic Neighbour Embedding (tSNE) analysis of DNA methylation profiles regrouped BRAFV600E and all but one FGFR1MUT DMG in a unique methylation cluster, distinct from the other DMG subgroups and also from ganglioglioma (GG) or high-grade astrocytoma with piloid features (HGAP). This new DMG subtype harbours atypical radiological and histopathological profiles with calcification and/or a solid tumour component both for BRAFV600E and FGFR1MUT cases. The analyses of a H3.3-K27M BRAFV600E tumour at diagnosis and corresponding in vitro cellular model showed that mutation in H3-3A was the first event in the oncogenesis. Contrary to other DMG, these tumours occur more frequently in the thalamus (70% for BRAFV600E and 58% for FGFR1MUT) and patients have a longer overall survival with a median above three years. In conclusion, DMG, H3 K27 and BRAF/FGFR1 co-altered represent a new subtype of DMG with distinct genotype/phenotype characteristics, which deserve further attention with respect to trial interpretation and patient management.
    Keywords:  Adult glioma; BRAF-V600E mutation; DNA methylation profiling; FGFR1 mutation; Midline glioma; Paediatric-type high-grade glioma
    DOI:  https://doi.org/10.1007/s00401-023-02651-4
  6. Neuro Oncol. 2023 Dec 09. pii: noad233. [Epub ahead of print]
    Cholesterol homeostasis confers glioma malignancy triggered by hnRNPA2B1-dependent regulation of SREBP2 and LDLR.
    Juan Zhang, Bei Liu, Changwei Xu, Chenchen Ji, Anan Yin, Yifeng Liu, Yan Yao, Bowen Li, Tangdong Chen, Liangliang Shen, Yuanming Wu.
       BACKGROUND: Dysregulation of cholesterol metabolism is a significant characteristic of glioma, yet the underlying mechanisms are largely unknown. N6-methyladenosine (m6A) modification has been implicated in promoting tumor development and progression. The aim of this study was to determine the key m6A regulatory proteins involved in the progression of glioma, which is potentially associated with the reprogramming of cholesterol homeostasis.
    METHODS: Bioinformatics analysis was performed to determine the association of m6A modification with glioma malignancy from TCGA and GTEx datasets. GSC self-renewal was determined by tumor sphere formation and bioluminescence image assay. RNA sequencing and lipidomic analysis were performed for cholesterol homeostasis analysis. RNA immunoprecipitation and luciferase reporter assay were performed to determine hnRNPA2B1-dependent regulation of SREBP2 and LDLR mRNA. The methylation status of hnRNPA2B1 promoter was determined by bioinformatic analysis and methylation-specific PCR assay.
    RESULTS: Among the m6A-regulatory proteins, hnRNPA2B1 was demonstrated the most important independent prognostic risk factor for glioma. hnRNPA2B1 ablation exhibited a significant tumor-suppressive effect on glioma cell proliferation, GSC self-renewal and tumorigenesis. hnRNPA2B1 triggers de novo cholesterol synthesis by inducing HMGCR through the stabilization of SREBP2 mRNA. m6A modification of SREBP2 or LDLR mRNA is required for hnRNPA2B1-mediated mRNA stability. The hypomethylation of cg21815882 site on hnRNPA2B1 promoter confers elevated expression of hnRNPA2B1 in glioma tissues. The combination of targeting hnRNPA2B1 and cholesterol metabolism exhibited remarkable anti-tumor effects, suggesting valuable clinical implications for glioma treatment.
    CONCLUSIONS: hnRNPA2B1 facilitates cholesterol uptake and de novo synthesis, thereby contributing to glioma stemness and malignancy.
    Keywords:  Cholesterol homeostasis; glioma stem cell; hnRNPA2B1; m6A modification
    DOI:  https://doi.org/10.1093/neuonc/noad233
  7. Neuro Oncol. 2023 Dec 12. pii: noad243. [Epub ahead of print]
    Visualizing Cancer-Originating Acetate Uptake Through MCT1 in Reactive Astrocytes in the Glioblastoma Tumor Microenvironment.
    Dongwoo Kim, Hae Young Ko, Jee-In Chung, Yongmin Mason Park, Sangwon Lee, Seon Yoo Kim, Jisu Kim, Joong-Hyun Chun, Kyung-Seok Han, Misu Lee, Yeon Ha Ju, Sun Jun Park, Ki Duk Park, Min-Ho Nam, Se Hoon Kim, Jin-Kyoung Shim, Youngjoo Park, Hyunkeong Lim, Jaekyung Park, Hyunjin Kim, Suhyun Kim, Uiyeol Park, Hoon Ryu, So Yun Lee, Sunghyouk Park, Seok-Gu Kang, Jong Hee Chang, C Justin Lee, Mijin Yun.
       BACKGROUND: Reactive astrogliosis is a hallmark of various brain pathologies, including neurodegenerative diseases and glioblastomas. However, the specific intermediate metabolites contributing to reactive astrogliosis remain unknown. This study investigated how glioblastomas induce reactive astrogliosis in the neighboring microenvironment and explores 11C-acetate PET as an imaging technique for detecting reactive astrogliosis.
    METHODS: Through in vitro, mouse models, and human tissue experiments, we examined the association between elevated 11C-acetate uptake and reactive astrogliosis in gliomas. We explored acetate from glioblastoma cells, which triggers reactive astrogliosis in neighboring astrocytes by upregulating MAO-B and MCT1 expression. We evaluated the presence of cancer stem cells in the reactive astrogliosis region of glioblastomas and assessed the correlation between the volume of 11C-acetate uptake beyond MRI and prognosis.
    RESULTS: Elevated 11C-acetate uptake is associated with reactive astrogliosis and astrocytic MCT1 in the periphery of glioblastomas in human tissues and mouse models. Glioblastoma cells exhibit increased acetate production as a result of glucose metabolism, with subsequent secretion of acetate. Acetate derived from glioblastoma cells induces reactive astrogliosis in neighboring astrocytes by increasing the expression of MAO-B and MCT1. We found cancer stem cells within the reactive astrogliosis at the tumor periphery. Consequently, a larger volume of 11C-acetate uptake beyond contrast-enhanced MRI was associated with worse prognosis.
    CONCLUSION: Our results highlight the role of acetate derived from glioblastoma cells in inducing reactive astrogliosis and underscore the potential value of 11C-acetate PET as an imaging technique for detecting reactive astrogliosis, offering important implications for the diagnosis and treatment of glioblastomas.
    Keywords:  PET imaging; acetate; glioblastoma; monocarboxylate transporter 1; reactive astrogliosis
    DOI:  https://doi.org/10.1093/neuonc/noad243
  8. Neuro Oncol. 2023 Dec 14. pii: noad229. [Epub ahead of print]
    Liquid Biopsy in H3K27M Diffuse Midline Glioma.
    Jina Patel, Rayan Aittaleb, Robert Doherty, Ananya Gera, Benison Lau, Dana Messinger, Jack Wadden, Andrea Franson, Amanda Saratsis, Carl Koschmann.
      Diffuse midline glioma (DMG) with H3K27M mutation is an aggressive and difficult to treat pediatric brain tumor. Recurrent gain of function mutations in H3.3 (H3.3A) and H3.1 (H3C2) at the 27th lysine to methionine (H3K27M) are seen in over 2/3 of DMGs, and are associated with a worse prognosis. Due to the anatomical location of DMG, traditional biopsy carries risk for neurologic injury as it requires penetration of vital midline structures. Further, radiographic (MRI) monitoring of DMG often shows non-specific changes, which makes therapeutic monitoring difficult. This indicates a critical need for more minimally invasive methods, such as liquid biopsy, to understand, diagnose, and monitor H3K27M DMG. Here we review the use of all modalities to date to detect biomarkers of H3K27M in CSF, blood, and urine, and compare their effectiveness in detection, diagnosis, and monitoring treatment response. We provide specific detail of recent efforts to monitor CSF and plasma H3K27M cell-free DNA in patients undergoing therapy with the imipridone ONC201. Lastly, we discuss the future of therapeutic monitoring of H3K27M-DMG, including biomarkers such as mitochondrial DNA, mutant and modified histones, and novel sequencing-based approaches for improved detection methods.
    Keywords:  H3K27M; Liquid biopsy; ONC201; cell-free tumor DNA; diffuse midline glioma
    DOI:  https://doi.org/10.1093/neuonc/noad229
  9. Cell Death Dis. 2023 Dec 13. 14(12): 821
    Chlorpromazine affects glioblastoma bioenergetics by interfering with pyruvate kinase M2.
    Claudia Abbruzzese, Silvia Matteoni, Paola Matarrese, Michele Signore, Barbara Ascione, Elisabetta Iessi, Aymone Gurtner, Andrea Sacconi, Lucia Ricci-Vitiani, Roberto Pallini, Andrea Pace, Veronica Villani, Andrea Polo, Susan Costantini, Alfredo Budillon, Gennaro Ciliberto, Marco G Paggi.
      Glioblastoma (GBM) is the most frequent and lethal brain tumor, whose therapeutic outcome - only partially effective with current schemes - places this disease among the unmet medical needs, and effective therapeutic approaches are urgently required. In our attempts to identify repositionable drugs in glioblastoma therapy, we identified the neuroleptic drug chlorpromazine (CPZ) as a very promising compound. Here we aimed to further unveil the mode of action of this drug. We performed a supervised recognition of the signal transduction pathways potentially influenced by CPZ via Reverse-Phase Protein microArrays (RPPA) and carried out an Activity-Based Protein Profiling (ABPP) followed by Mass Spectrometry (MS) analysis to possibly identify cellular factors targeted by the drug. Indeed, the glycolytic enzyme PKM2 was identified as one of the major targets of CPZ. Furthermore, using the Seahorse platform, we analyzed the bioenergetics changes induced by the drug. Consistent with the ability of CPZ to target PKM2, we detected relevant changes in GBM energy metabolism, possibly attributable to the drug's ability to inhibit the oncogenic properties of PKM2. RPE-1 non-cancer neuroepithelial cells appeared less responsive to the drug. PKM2 silencing reduced the effects of CPZ. 3D modeling showed that CPZ interacts with PKM2 tetramer in the same region involved in binding other known activators. The effect of CPZ can be epitomized as an inhibition of the Warburg effect and thus malignancy in GBM cells, while sparing RPE-1 cells. These preclinical data enforce the rationale that allowed us to investigate the role of CPZ in GBM treatment in a recent multicenter Phase II clinical trial.
    DOI:  https://doi.org/10.1038/s41419-023-06353-3
  10. Cancer Res. 2023 Dec 14.
    Fimepinostat impairs NF-κB and PI3K/AKT signaling and enhances gemcitabine efficacy in H3K27M-mutated diffuse intrinsic pontine glioma.
    Dan Wang, Kun Yan, Hongxing Yu, Haocheng Li, Wei Zhou, Yaqiang Hong, Shuning Guo, Yi Wang, Cheng Xu, Changcun Pan, Yujie Tang, Nian Liu, Wei Wu, Liwei Zhang, Qiaoran Xi.
      Diffuse intrinsic pontine glioma (DIPG) is the most aggressive pediatric brain tumor, and the oncohistone H3.3K27M mutation is associated with significantly worse clinical outcomes. Despite extensive research efforts, effective approaches for treating DIPG are lacking. Through drug screening, we identified the combination of gemcitabine and fimepinostat as a potent therapeutic intervention for H3.3K27M DIPG. H3.3K27M facilitated gemcitabine-induced apoptosis in DIPG, and gemcitabine stabilized and activated p53, including increasing chromatin accessibility for p53 at apoptosis-related loci. Gemcitabine simultaneously induced a pro-survival program in DIPG through activation of RELB-mediated NF-κB signaling. Specifically, gemcitabine induced the transcription of long terminal repeat elements, activated cGAS-STING signaling, and stimulated non-canonical NF-κB signaling. A drug screen in gemcitabine-treated DIPG cells revealed that fimepinostat, a dual inhibitor of HDAC and PI3K, effectively suppressed the gemcitabine-induced NF-κB signaling in addition to blocking PI3K/AKT activation. Combination therapy comprising gemcitabine and fimepinostat elicited synergistic anti-tumor effects in vitro and in orthotopic H3.3K27M DIPG xenograft models. Collectively, p53 activation using gemcitabine and suppression of RELB-mediated NF-κB activation and PI3K/AKT signaling using fimepinostat is a potential therapeutic strategy for treating H3.3K27M DIPG.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-23-0394
  11. Neuro Oncol. 2023 Dec 09. pii: noad240. [Epub ahead of print]
    The potential of amino acid PET imaging for prediction and monitoring of vorasidenib response in IDH-mutant gliomas.
    Nathalie L Albert, Julia Furtner, Martin J van den Bent, Matthias Preusser.
      
    DOI:  https://doi.org/10.1093/neuonc/noad240
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