bims-malgli Biomed News
on Biology of malignant gliomas
Issue of 2024–11–03
ten papers selected by
Oltea Sampetrean, Keio University
  1. NF1 expression profiling in IDH-wildtype glioblastoma: genomic associations and survival outcomes.
  2. Modeling Glioma Intratumoral Heterogeneity with Primary Human Neural Stem and Progenitor Cells.
  3. The self-organized structure of glioma oncostreams and the disruptive role of passive cells.
  4. Protumoral lipid droplet-loaded macrophages are enriched in human glioblastoma and can be therapeutically targeted.
  5. Metabolic regulation of the glioblastoma stem cell epitranscriptome by malate dehydrogenase 2.
  6. Glioma immune microenvironment composition calculator (GIMiCC): a method of estimating the proportions of eighteen cell types from DNA methylation microarray data.
  7. Dual phenotypes in recurrent astrocytoma, IDH-mutant; coexistence of IDH-mutant and IDH-wildtype components: a case report with genetic and epigenetic analysis.
  8. Imaging PD-L1 in the brain-Journey from the lab to the clinic.
  9. Current research status of Raman spectroscopy in glioma detection.
  10. EVA1-Antibody Drug Conjugate is a new therapeutic strategy for eliminating glioblastoma-initiating cells.
  1. Acta Neuropathol Commun. 2024 Oct 29. 12(1): 172
    NF1 expression profiling in IDH-wildtype glioblastoma: genomic associations and survival outcomes.
    Michael Chang, Mohamed Sherief, Maria Ioannou, Viveka Chinnasamy, Lucy Chen, Michael Frost, Michelle Mattson-Hoss, Herb Sarnoff, David O Kamson, Matthias Holdhoff, Debraj Mukherjee, Chetan Bettegowda, Jordina Rincon-Torroella, Victoria Croog, Peng Huang, Fausto J Rodriguez, Calixto-Hope G Lucas, Karisa C Schreck.
       BACKGROUND: NF1 inactivation is associated with sensitivity to MEK inhibitor targeted therapy in low-grade and some high-grade gliomas. NF1 loss may also be a harbinger of exploitable vulnerabilities in IDH-wildtype glioblastoma (GBM). Accurate and consistent detection of NF1 loss, however, is fraught given the large gene size, challenges with complete coverage and variant calling upon sequencing, and mechanisms of mRNA and protein regulation that result in early degradation in the absence of genomic alterations. Here, we seek to perform a composite analysis for NF1 loss accounting for genomic alterations and protein expression via immunohistochemistry. We also characterize the landscape of NF1 alterations in GBM.
    METHODS: We assembled a single-institution, retrospective cohort of 542 IDH-wildtype GBM with somatic next generation sequencing to investigate the frequency and nature of detected NF1 alterations. We selected 69 GBMs from which to build a tissue microarray (TMA) of 44 NF1-wildtype and 25 NF1-mutant cases. We performed NF1 immunohistochemistry using two different NF1 antibodies (NFC, Sigma-Aldrich; and iNF-07E, iNFixion Bioscience) and correlated results with clinical, genomic, and other immunohistochemical features.
    RESULTS: In our retrospective cohort, we identified 88 IDH-wildtype GBM with NF1 alterations (16%). NF1 alterations were mutually exclusive with EGFR and MDM2 alterations (p-adj < 0.001, 0.05, respectively), but co-occurred with PIK3R1 alterations (Log2(OR) = - 1.6, p-adj = 0.03). Of the 63 scorable sporadic GBMs in the TMA, 14 harbored NF1 inactivating alterations and of those, 12 (86%) demonstrated minimal NF1 immunoreactivity by NFC antibody, compared to 8 (57%) by iNF-07E antibody. Among the 42 scorable NF1-wildtype GBM in the TMA, NF1 immunostaining was minimal in 18 (43%) by NFC antibody compared to 4 (10%) by iNF-07E antibody, potentially reflecting false positives or differential protein regulation. Minimal immunoreactivity by NFC antibody was associated with decreased median overall survival (8.5 vs. 16.4 months, p = 0.011). Cox proportional hazards model correcting for prognostic variables in this subset revealed HR 3.23 (95% CI 1.29-8.06, p = 0.01) associated with decreased NF1 expression by IHC.
    CONCLUSION: NF1 immunostaining may serve as a sensitive surrogate marker of NF1 genomic inactivation and a valuable extension to next-generation sequencing for defining NF1 status. Minimal NF1 immunoreactivity is a poor prognostic marker, even in IDH-wildtype glioblastoma without apparent NF1 genomic alterations, but the underlying molecular mechanism requires further investigation.
    Keywords:  Biomarker; Glioblastoma; High-grade glioma; NF1; Neurofibromin
    DOI:  https://doi.org/10.1186/s40478-024-01875-z
  2. bioRxiv. 2024 Oct 22. pii: 2024.10.20.619254. [Epub ahead of print]
    Modeling Glioma Intratumoral Heterogeneity with Primary Human Neural Stem and Progenitor Cells.
    Daniel Gao, Daniel Dan Liu, Anna E Eastman, Nicole L Womack, Benjamin F Ohene-Gambill, Michelle Baez, Irving L Weissman.
      Glioblastoma multiforme (GBM) is a deadly form of glioma notable for its significant intratumoral heterogeneity, which is believed to drive therapy resistance. GBM has been observed to mimic a neural stem cell hierarchy reminiscent of normal brain development. However, it is still unclear how cell-of-origin shapes intratumoral heterogeneity. Here, we develop a model of glioma initiation using neural stem and progenitor cells (NSPCs) purified from fetal human brain tissue. We previously described a method to prospectively isolate and culture tripotent neural stem cells (NSCs), bipotent glial progenitor cells (GPCs), and unipotent oligodendrocyte precursor cells (OPCs). We transduced these isogenic lines with dominant-negative TP53 R175H and NF1 knockdown, a commonly-used genetic model of GBM in mice. These reprogrammed lines robustly engrafted when transplanted into the brains of immunodeficient mice, and showed significant expansion over time. Engrafted cells were reextracted from the mouse brain for single cell RNA sequencing (scRNA-seq), in order to quantify how the cell-of-origin modulates the cellular subtypes found in the resulting tumor. This result revealed the strong influence the cell-of-origin plays in glioma heterogeneity. Our platform is highly adaptable and allows for modular and systematic interrogation of how cell-of-origin shape the tumor landscape.
    DOI:  https://doi.org/10.1101/2024.10.20.619254
  3. Sci Rep. 2024 10 25. 14(1): 25435
    The self-organized structure of glioma oncostreams and the disruptive role of passive cells.
    Lucas Barberis, Carlos A Condat, Syed M Faisal, Pedro R Lowenstein.
      Oncostreams are self-organized structures formed by spindle-like, elongated, self-propelled cells recently described in glioblastomas and especially in gliosarcomas. Cells within these structures either move as large clusters in one main direction, flocks, or as linear, intermingling collections of cells advancing in opposite directions, streams. Round, passive cells are also observed, either inside or segregated from the oncostreams. Here we generalize a recently formulated particle-field approach to investigate the genesis and evolution of these structures, first showing that, in systems consisting only of identical self-propelled cells, both flocks and streams emerge as self-organized dynamic configurations. Flocks are the more stable configurations, while streams are transient and usually originate in collisions between flocks. Stream degradation is easier at low self-propulsion speeds. In systems consisting of both motile and passive cells, the latter block stream formation and accelerate their degradation and flock stabilization. Since the flock appears to be the most effective invasive structure, we thus argue that a phenotype mixture (motile and passive cells) may favor glioblastoma invasion. hlBy relating cellular properties to the observed outcome, our model shows that oncostreams are self-organized structures that result from the interplay between speed, shape, and steric repulsion.
    Keywords:  Active matter; Active nematics; Glioma; Oncostream; Self-organization
    DOI:  https://doi.org/10.1038/s41598-024-74823-5
  4. Sci Transl Med. 2024 Oct 30. 16(771): eadk1168
    Protumoral lipid droplet-loaded macrophages are enriched in human glioblastoma and can be therapeutically targeted.
    Valeria Governa, Kelin Gonçalves de Oliveira, Anna Bång-Rudenstam, Svenja Offer, Myriam Cerezo-Magaña, Jiaxin Li, Sarah Beyer, Maria C Johansson, Ann-Sofie Månsson, Charlotte Edvardsson, Faris Durmo, Emma Gustafsson, Axel Boukredine, Pauline Jeannot, Katja Schmidt, Emelie Gezelius, Julien A Menard, Raquel Garza, Johan Jakobsson, Therese de Neergaard, Pia C Sundgren, Aliisa M Tiihonen, Hannu Haapasalo, Kirsi J Rautajoki, Pontus Nordenfelt, Anna Darabi, Karin Forsberg-Nilsson, Alexander Pietras, Hugo Talbot, Johan Bengzon, Mattias Belting.
      Glioblastoma presents a formidable clinical challenge because of its complex microenvironment. Here, we characterized tumor-associated foam cells (TAFs), a type of lipid droplet-loaded macrophage, in human glioblastoma. Through extensive analyses of patient tumors, together with in vitro and in vivo investigations, we found that TAFs exhibit distinct protumorigenic characteristics related to hypoxia, mesenchymal transition, angiogenesis, and impaired phagocytosis, and their presence correlates with worse outcomes for patients with glioma. We further demonstrated that TAF formation is facilitated by lipid scavenging from extracellular vesicles released by glioblastoma cells. We found that targeting key enzymes involved in lipid droplet formation, such as diacylglycerol O-acyltransferase or long-chain acyl-CoA synthetase, effectively disrupted TAF functionality. Together, these data highlight TAFs as a prominent immune cell population in glioblastoma and provide insights into their contribution to the tumor microenvironment. Disrupting lipid droplet formation to target TAFs may represent an avenue for future therapeutic development for glioblastoma.
    DOI:  https://doi.org/10.1126/scitranslmed.adk1168
  5. Cell Metab. 2024 Oct 19. pii: S1550-4131(24)00396-6. [Epub ahead of print]
    Metabolic regulation of the glioblastoma stem cell epitranscriptome by malate dehydrogenase 2.
    Deguan Lv, Deobrat Dixit, Andrea F Cruz, Leo J Y Kim, Likun Duan, Xin Xu, Qiulian Wu, Cuiqing Zhong, Chenfei Lu, Zachary C Gersey, Ryan C Gimple, Qi Xie, Kailin Yang, Xiaojing Liu, Xiaoguang Fang, Xujia Wu, Reilly L Kidwell, Xiuxing Wang, Shideng Bao, Housheng H He, Jason W Locasale, Sameer Agnihotri, Jeremy N Rich.
      Tumors reprogram their metabolism to generate complex neoplastic ecosystems. Here, we demonstrate that glioblastoma (GBM) stem cells (GSCs) display elevated activity of the malate-aspartate shuttle (MAS) and expression of malate dehydrogenase 2 (MDH2). Genetic and pharmacologic targeting of MDH2 attenuated GSC proliferation, self-renewal, and in vivo tumor growth, partially rescued by aspartate. Targeting MDH2 induced accumulation of alpha-ketoglutarate (αKG), a critical co-factor for dioxygenases, including the N6-methyladenosine (m6A) RNA demethylase AlkB homolog 5, RNA demethylase (ALKBH5). Forced expression of MDH2 increased m6A levels and inhibited ALKBH5 activity, both rescued by αKG supplementation. Reciprocally, targeting MDH2 reduced global m6A levels with platelet-derived growth factor receptor-β (PDGFRβ) as a regulated transcript. Pharmacological inhibition of MDH2 in GSCs augmented efficacy of dasatinib, an orally bioavailable multi-kinase inhibitor, including PDGFRβ. Collectively, stem-like tumor cells reprogram their metabolism to induce changes in their epitranscriptomes and reveal possible therapeutic paradigms.
    Keywords:  ALKBH5; MDH2; PDGFRβ; alpha-ketoglutarate; cancer stem cell; epitranscriptomics; glioblastoma; m6A; malate-aspartate shuttle; metabolism
    DOI:  https://doi.org/10.1016/j.cmet.2024.09.014
  6. Acta Neuropathol Commun. 2024 Oct 28. 12(1): 170
    Glioma immune microenvironment composition calculator (GIMiCC): a method of estimating the proportions of eighteen cell types from DNA methylation microarray data.
    Steven C Pike, John K Wiencke, Ze Zhang, Annette M Molinaro, Helen M Hansen, Devin C Koestler, Brock C Christensen, Karl T Kelsey, Lucas A Salas.
      A scalable platform for cell typing in the glioma microenvironment can improve tumor subtyping and immune landscape detection as successful immunotherapy strategies continue to be sought and evaluated. DNA methylation (DNAm) biomarkers for molecular classification of tumor subtypes have been developed for clinical use. However, tools that predict the cellular landscape of the tumor are not well-defined or readily available. We developed the Glioma Immune Microenvironment Composition Calculator (GIMiCC), an approach for deconvolution of cell types in gliomas using DNAm data. Using data from 17 isolated cell types, we describe the derivation of the deconvolution libraries in the biological context of selected genomic regions and validate deconvolution results using independent datasets. We utilize GIMiCC to illustrate that DNAm-based estimates of immune composition are clinically relevant and scalable for potential clinical implementation. In addition, we utilize GIMiCC to identify composition-independent DNAm alterations that are associated with high immune infiltration. Our future work aims to optimize GIMiCC and advance the clinical evaluation of glioma.
    Keywords:  DNA methylation; Deconvolution; Epidemiology; Glioma; Tumor microenvironment
    DOI:  https://doi.org/10.1186/s40478-024-01874-0
  7. Acta Neuropathol Commun. 2024 Oct 26. 12(1): 169
    Dual phenotypes in recurrent astrocytoma, IDH-mutant; coexistence of IDH-mutant and IDH-wildtype components: a case report with genetic and epigenetic analysis.
    Junya Yamaguchi, Fumiharu Ohka, Masafumi Seki, Kazuya Motomura, Shoichi Deguchi, Yoshiki Shiba, Yuka Okumura, Yuji Kibe, Hiroki Shimizu, Sachi Maeda, Yuhei Takido, Ryo Yamamoto, Akihiro Nakamura, Kennosuke Karube, Ryuta Saito.
      Mutations in the isocitrate dehydrogenase (IDH) gene are recognized as the key drivers in the oncogenesis of astrocytoma and oligodendroglioma. However, the significance of IDH mutation in tumor maintenance and malignant transformation has not been elucidated. We encountered a unique case of IDH-mutant astrocytoma that, upon malignant transformation, presented two distinct intratumoral components: one IDH-wildtype and one IDH-mutant. The IDH-wild-type component exhibited histological findings similar to those of small cell-type glioblastoma with a higher Ki-67 index than the IDH-mutant component. Despite their genetic divergence, both components exhibited similar comprehensive methylation profiles within the CpG island and were classified into methylation class of "Astrocytoma, IDH-mutant; High Grade" by the German Cancer Center (DKFZ) classifier v11.4. Phylogenetic analysis demonstrated that the IDH-wildtype component emerged as a subclonal component of the primary tumor. Detailed molecular analyses revealed that the loss of the IDH mutation was induced by the hemizygous loss of the entire arm of chromosome 2, on which IDH1 gene is located. Notably, the IDH-wild-type subclones uniquely acquired CDKN2A/B homozygous deletion and PDGFRA amplification, which is a marker of the aggressive phenotype of astrocytoma, IDH-mutant. Because these genetic abnormalities can drive oncogenic pathways, such as the PI3K/AKT/mTOR and RB signaling pathway, IDH-mutant gliomas that acquired these mutations were no longer dependent on the initial driver mutation, the IDH mutation. Molecular analysis of this unique case provides insight that in a subset of astrocytoma, IDH-mutant that acquired these genetic abnormalities, IDH mutation may not play a pivotal role in tumor growth and acquisition of these genetic abnormalities may contribute to the acquisition of resistance to IDH inhibitors.
    Keywords:   CDKN2A/B homozygous deletion; PDGFRA amplification; Astrocytoma; Loss of IDH mutation; Methylation analysis
    DOI:  https://doi.org/10.1186/s40478-024-01879-9
  8. Neuro Oncol. 2024 Oct 28. pii: noae190. [Epub ahead of print]
    Imaging PD-L1 in the brain-Journey from the lab to the clinic.
    Dawoud Dar, Magdalena Rodak, Chiara Da Pieve, Izabela Gorczewska, Gitanjali Sharma, Ewa Chmielik, Marcin Niedbala, Pawel Bzowski, Andrea d'Amico, Barbara Bobek-Billewicz, Elzbieta Nowicka, Rafal Tarnawski, Wojciech Kaspera, Gabriela Kramer-Marek.
       BACKGROUND: Immune checkpoint inhibitors (ICPIs) have proven to restore adaptive anti-tumor immunity in many cancers; however, no noteworthy therapeutic schedule has been established for patients with glioblastoma (GBM). High programmed death-ligand 1 (PD-L1) expression is associated with immunosuppressive and aggressive phenotypes in GBM. Presently, there is no standardized protocol for assessing PD-L1 expression levels to select patients and monitor their response to ICPI therapy. The aim of this study was to investigate the use of 89Zr-DFO-Atezolizumab to image the spatio-temporal distribution of PD-L1 in preclinical mouse models and in patients with newly diagnosed GBM treated with/without neoadjuvant Pembrolizumab.
    METHODS: The immunoreactivity, binding affinity, and specificity of 89Zr-DFO-Atezolizumab were confirmed in vitro. Mice-bearing orthotopic GBM tumors or patients with newly diagnosed GBM treated with/without Pembrolizumab were intravenously injected with 89Zr-DFO-Atezolizumab, and PET/CT images were acquired 24, 48, and 72 hours in mice and at 48 and 72 post-injection in patients. Radioconjugate uptake was quantified in the tumor and healthy tissues. Ex vivo immunohistochemistry (IHC) and immunophenotyping were performed on mouse tumor samples or resected human tumors.
    RESULTS: 89Zr-DFO-Atezolizumab was prepared with high radiochemical purity (RCP > 99%). In vitro cell-associated radioactivity of 89Zr-DFO-Atezolizumab corroborated cell line PD-L1 expression. PD-L1 in mouse GBM tumors was detected with high specificity using 89Zr-DFO-Atezolizumab and radioconjugate uptake correlated with IHC. Patients experienced no 89Zr-DFO-Atezolizumab-related side effects. High 89Zr-DFO-Atezolizumab uptake was observed in patient tumors at 48 hours post-injection, however, the uptake varied between patients treated with/without Pembrolizumab.
    CONCLUSIONS: 89Zr-DFO-Atezolizumab can visualize distinct PD-L1 expression levels with high specificity in preclinical mouse models and in patients with GBM, whilst complementing ex vivo analysis.
    Keywords:  glioblastoma; immuno-PET; immunotherapy; nuclear medicine; translational studies
    DOI:  https://doi.org/10.1093/neuonc/noae190
  9. Photodiagnosis Photodyn Ther. 2024 Oct 24. pii: S1572-1000(24)00425-3. [Epub ahead of print] 104388
    Current research status of Raman spectroscopy in glioma detection.
    Jie Liu, Pan Wang, Hua Zhang, Yuansen Guo, Mingjie Tang, Junwei Wang, Nan Wu.
      Glioma is the most common primary tumor of the nervous system. Conventional diagnostic methods for glioma often involve time-consuming or reliance on externally introduced materials. Consequently, there is an urgent need for rapid and reliable diagnostic techniques. Raman spectroscopy has emerged as a promising tool, offering rapid, accurate, and label-free analysis with high sensitivity and specificity in biomedical applications. In this review, the fundamental principles of Raman spectroscopy have been introduced, and then the progress of applying Raman spectroscopy in biomedical studies has been summarized, including the identification and typing of glioma. The challenges encountered in the clinical application of Raman spectroscopy for glioma have been discussed, and the prospects have also been envisioned.
    Keywords:  Glioma detection; Histological typing; Molecular typing; Raman spectroscopy
    DOI:  https://doi.org/10.1016/j.pdpdt.2024.104388
  10. Neuro Oncol. 2024 Oct 29. pii: noae226. [Epub ahead of print]
    EVA1-Antibody Drug Conjugate is a new therapeutic strategy for eliminating glioblastoma-initiating cells.
    Jiahui Hou, Tamami Uejima, Miho Tanaka, You Lee Son, Kazuharu Hanada, Mutsuko Kukimoto-Niino, Shigeru Yamaguchi, Shigeru Hashimoto, Shigeyuki Yokoyama, Toshitada Takemori, Takashi Saito, Mikako Shirouzu, Toru Kondo.
       BACKGROUND: The discovery of glioblastoma (GBM)-initiating cells (GICs) has impacted GBM research. These cells are not only tumorigenic, but also exhibit resistance to radiotherapy and chemotherapy. Therefore, it is crucial to characterize GICs thoroughly and identify new therapeutic targets. In a previous study, we successfully identified Epithelial V-like antigen 1 (EVA1) as a novel functional factor specific to GICs.
    METHODS: Hybridoma cells were generated by immunizing BALB/c mice with EVA1-Fc fusion protein. The reactivity of the supernatant from these hybridoma cells was examined using EVA1-overexpressing cells and GICs. Candidate antibodies were further selected using Biacore surface plasmon resonance analysis and two cytotoxicity assays, antibody-dependent cell cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC). Among the antibodies, the cytotoxicity of the B2E5-antibody drug conjugate (B2E5-ADC) was evaluated by both adding it to cultured GICs and injecting it into GIC tumor-bearing brains.
    RESULTS: B2E5 demonstrated a high affinity for human EVA1 and effectively killed both EVA1-expressing cell lines and GICs in culture through ADCC and CDC. B2E5-ADC also exhibited strong cytotoxicity to GICs in culture and prevented their tumorigenesis in the brain when administered intracranially to the tumor-bearing brain.
    CONCLUSION: Our data indicate that B2E5-ADC is a new and promising therapeutic strategy for GBM.
    Keywords:  ADC; B2E5; EVA1; GBM-initiating cell (GIC); Glioblastoma (GBM)
    DOI:  https://doi.org/10.1093/neuonc/noae226
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