bims-malgli Biomed News
on Biology of malignant gliomas
Issue of 2022‒03‒20
eleven papers selected by
Oltea Sampetrean
Keio University

  1. Neuro Oncol. 2022 Mar 14. pii: noac063. [Epub ahead of print]
      BACKGROUND: Glioblastoma stem cells (GSCs) and their interplay with tumor-associated macrophages (TAMs) are responsible for malignant growth and tumor recurrence of Glioblastoma (GBM), but the underlying mechanisms are largely unknown.METHODS: Cell viability, stemness, migration and invasion was measured in GSCs after knockdown of upstream stimulating factor 1 (USF1). Luciferase assay and chromatin immunoprecipitation qPCR were performed to determine the regulation of CD90 by USF1. Immunohistochemistry and immunofluorescent staining were used to examine the expression of USF1 and GSC markers, as well as the crosstalk between GSCs and TAMs. In addition, the interaction between GSCs and TAMs was confirmed using in vivo GBM models.
    RESULTS: We show that USF1 promotes malignant glioblastoma phenotypes and GSCs-TAMs physical interaction by inducing CD90 expression. USF1 predicts a poor prognosis for glioma patients, and is upregulated in patient-derived GSCs and glioblastoma cell lines. USF1 overexpression increases the proliferation, invasion and neurosphere formation of GSCs and glioblastoma cell lines, while USF1 knockdown exerts an opposite effect. Further mechanistic studies reveal that USF1 promotes GSC's stemness by directly regulating CD90 expression. Importantly, CD90 of GSCs functions as an anchor for physical interaction with macrophage. Additionally, the USF1/CD90 signaling axis supports the GSCs and TAMs adhesion and immunosuppressive feature of TAMs, which in turn enhance the stemness of GSCs. Moreover, the overexpression of CD90 restores the stemness property in USF1 knockdown GSCs and its immunosuppressive microenvironment.
    CONCLUSIONS: Our findings indicate that the USF1/CD90 axis might be a potential therapeutic target for the treatment of glioblastoma.
    Keywords:  CD90; GBM; Glioblastoma stem cells; USF1; stemness
  2. Neurooncol Adv. 2022 Jan-Dec;4(1):4(1): vdac008
      The response assessment in neuro-oncology (RANO) criteria have been the gold standard for monitoring treatment response in glioblastoma (GBM) and differentiating tumor progression from pseudoprogression. While the RANO criteria have played a key role in detecting early tumor progression, their ability to identify pseudoprogression is limited by post-treatment damage to the blood-brain barrier (BBB), which often leads to contrast enhancement on MRI and correlates poorly to tumor status. Amino acid positron emission tomography (AA PET) is a rapidly growing imaging modality in neuro-oncology. While contrast-enhanced MRI relies on leaky vascularity or a compromised BBB for delivery of contrast agents, amino acid tracers can cross the BBB, making AA PET particularly well-suited for monitoring treatment response and diagnosing pseudoprogression. The authors performed a systematic review of PubMed, MEDLINE, and Embase through December 2021 with the search terms "temozolomide" OR "Temodar," "glioma" OR "glioblastoma," "PET," and "amino acid." There were 19 studies meeting inclusion criteria. Thirteen studies utilized [18F]FET, five utilized [11C]MET, and one utilized both. All studies used static AA PET parameters to evaluate TMZ treatment in glioma patients, with nine using dynamic tracer parameters in addition. Throughout these studies, AA PET demonstrated utility in TMZ treatment monitoring and predicting patient survival.
    Keywords:  amino acid PET; glioblastoma; glioma; pseudoprogression; temozolomide; treatment response
  3. Neurooncol Adv. 2022 Jan-Dec;4(1):4(1): vdac023
      Background: Nonenhancing glioma typically have a favorable outcome, but approximately 19-44% have a highly aggressive course due to a glioblastoma genetic profile. The aim of this retrospective study is to use physiological MRI parameters of both perfusion and diffusion to distinguish the molecular profiles of glioma without enhancement at presentation.Methods: Ninety-nine patients with nonenhancing glioma were included, in whom molecular status (including 1p/19q codeletion status and IDH mutation) and preoperative MRI (T2w/FLAIR, dynamic susceptibility-weighted, and diffusion-weighted imaging) were available. Tumors were segmented semiautomatically using ITK-SNAP to derive whole tumor histograms of relative Cerebral Blood Volume (rCBV) and Apparent Diffusion Coefficient (ADC). Tumors were divided into three clinically relevant molecular profiles: IDH mutation (IDHmt) with (n = 40) or without (n = 41) 1p/19q codeletion, and (n = 18) IDH-wildtype (IDHwt). ANOVA, Kruskal-Wallis, and Chi-Square analyses were performed using SPSS.
    Results: rCBV (mean, median, 75th and 85th percentile) and ADC (mean, median, 15th and 25th percentile) showed significant differences across molecular profiles (P < .01). Posthoc analyses revealed that IDHwt and IDHmt 1p/19q codeleted tumors showed significantly higher rCBV compared to IDHmt 1p/19q intact tumors: mean rCBV (mean, SD) 1.46 (0.59) and 1.35 (0.39) versus 1.08 (0.31), P < .05. Also, IDHwt tumors showed significantly lower ADC compared to IDHmt 1p/19q codeleted and IDHmt 1p/19q intact tumors: mean ADC (mean, SD) 1.13 (0.23) versus 1.27 (0.15) and 1.45 (0.20), P < .001).
    Conclusions: A combination of low ADC and high rCBV, reflecting high cellularity and high perfusion respectively, separates IDHwt from in particular IDHmt 1p/19q intact glioma.
    Keywords:  ADC; MRI; molecular profile; nonenhancing glioma; rCBV
  4. Brain Pathol. 2022 Mar 14. e13062
      Over the last decade, developments in molecular profiling have radically altered the diagnosis, classification, and management of numerous cancer types, with primary brain tumors being no exception. Although historically brain tumors have been classified based on their morphological characteristics, recent advances have allowed refinement of tumor classification based on molecular alterations. This shift toward molecular classification of primary brain tumors is reflected in the 2021 5th edition of the WHO classification of central nervous system tumors (WHO 2021). In this review, we will discuss the most recent updates to the classification of adult-type diffuse gliomas, a group of highly infiltrative and largely incurable CNS malignancies. It is our hope continued that refinement of molecular criteria will improve diagnosis, prognostication, and eventually treatment of these devastating tumors.
    Keywords:  IDH; astrocytoma; glioblastoma; glioma; oligodendroglioma
  5. Neurooncol Adv. 2022 Jan-Dec;4(1):4(1): vdac018
      Background: Diffuse Midline Glioma, H3K27M-mutant (DMG) is a rare, highly aggressive pediatric tumor affecting the brainstem, and is one of the deadliest cancers. Currently available treatment options such as chemotherapy and radiotherapy do only modestly prolong survival. In this pathology, H3K27 mutations deregulate Polycomb Repressive Complex 2 (PRC2), including enzymatic activity of EZH2, which is therefore under investigation as a therapeutic target.Methods: We used a chemical EZH2 inhibitor, GSK126, small interfering RNAs, and a CRISPR/Cas9 knockout approaches in a series of DMG tumor cell lines to investigate metabolic treatment responses by proteomic analysis. A combination strategy was elaborated and studied in primary and established DMG cells, spheroid 3D cultures, and in vivo in a chick chorio-allantoic membrane DMG assay and an orthotopic intracranial DMG mouse model.
    Results: GSK126 shows significant (P < .05-.001) inhibitory effects in in vitro cell proliferation assays and induces apoptosis. Chemical targeting of EZH2 induced expression of proteins implicated in cholesterol metabolism. Low-dose GSK126 treatment together with statins revealed strong growth inhibition in combinatorial treatments, but not in single treatments, both in DMG cells in vitro, in DMG spheroid cultures, and in chick and mouse in vivo models (P < .05). All statistical tests were two-sided.
    Conclusions: Our results reveal an unexpected GSK126-inducible sensitivity to cholesterol biosynthesis inhibitors in highly aggressive pediatric glioma that warrants further evaluation as treatment strategy. This combinatorial therapy should have few side effects because of the low doses used to achieve significant anti-tumor activity.
    Keywords:  DMG; EZH2; GSK126; H3K27M-mutant; atorvastatin; cholesterol metabolism; diffuse midline glioma; enhancer Of Zeste homolog 2
  6. Oncogene. 2022 Mar 12.
      Macrophage-mediated tumor cell phagocytosis and subsequent neoantigen presentation are critical for generating anti-tumor immunity. This study aimed to uncover the potential clinical value and molecular mechanisms of miRNA-22 (miR-22) in tumor cell phagocytosis via macrophages and more efficient T cell priming. We found that miR-22 expression was markedly downregulated in primary macrophages from glioma tissue samples compared to adjacent tissues. miR-22-overexpressing macrophages inhibited glioma cell proliferation and migration, respectively. miR-22 upregulation stimulated the phagocytic ability of macrophages, enhanced tumor cell phagocytosis, antigen presentation, and efficient T cell priming. Additionally, our data revealed that miR-22-overexpressing macrophages inhibited glioma formation in vivo, HDAC6 was a target, and NF-κB signaling was a pathway closely associated with miR-22 in tumor-associated macrophages (TAMs) of glioma. Our findings revealed the essential roles of miR-22 in tumor cell phagocytosis by macrophages and more efficient T cell priming, facilitating further research on phagocytic regulation to enhance the response to tumor immunotherapy.
  7. Neuro Oncol. 2022 Mar 14. pii: noac064. [Epub ahead of print]
      BACKGROUND: IDH-mutant diffuse gliomas are heterogeneous, and improved methods for optimal patient therapeutic stratification are needed. PI3K/AKT/mTOR signaling activity can drive disease progression and potential therapeutic inhibitors of the pathway are available. Yet, the prevalence of PI3K/AKT/mTOR signaling pathway activity in IDH-mutant glioma is unclear and few robust strategies to assess activity in clinical samples exist.METHODS: PI3K/AKT/mTOR signaling pathway activity was evaluated in a retrospective cohort of 132 IDH-mutant diffuse glioma (91 astrocytoma and 41 oligodendroglioma, 1p/19q-codeleted) through quantitative multiplex immunoprofiling using phospho-specific antibodies for PI3K/AKT/mTOR pathway members, PRAS40, RPS6, and 4EBP1, and tumor-specific anti-IDH1 R132H. Expression levels were correlated with genomic evaluation of pathway intrinsic genes and univariate and multivariate Cox proportional hazard regression models were used to evaluate the relationship with outcome.
    RESULTS: Tumor-specific expression of p-PRAS40, p-RPS6, and p-4EBP1 was common in IDH-mutant diffuse glioma and increased with CNS WHO grade from 2 to 3. Genomic analysis predicted pathway activity in 21.7% (13/60) while protein evaluation identified active PI3K/AKT/mTOR signaling in 56.6% (34/60). Comparison of expression in male versus female patients suggested sexual dimorphism. Of particular interest, when adjusting for clinical prognostic factors, the level of phosphorylation of RPS6 was strongly associated with PFS (p < 0.005). Phosphorylation levels of both PRAS40 and RPS6 showed an association with PFS in univariate analysis.
    CONCLUSIONS: Our study emphasizes the value of proteomic assessment of signaling pathway activity in tumors as a means to identify relevant oncogenic pathways and potentially as a biomarker for identifying aggressive disease.
    Keywords:  PI3K/AKT/mTOR; biomarker; glioma; outcome; quantitative immunoprofiling
  8. Bioengineered. 2022 Mar;13(3): 7847-7859
      Gut microbiota is associated with the growth of various tumors, including malignant gliomas, through the brain-gut axis. Moreover, the gut microbiota in patients with malignant tumors may considerably differ from those with benign tumors. However, the associations of gut microbiota with benign and malignant brain tumors remain unclear. Hence, in order to explore these underlying relationships, patients with benign meningioma (n = 32), malignant glioma (n = 27), and healthy individuals (n = 41) were selected to participate in this study. The results showed that the diversity of the microbial ecosystem in brain tumor patients were less than the healthy controls, while no significant differences were observed between the meningioma and glioma groups. The microbial composition also differed significantly between individuals with brain tumors and healthy participants. In meningioma group, pathogenic bacteria like Enterobacteriaceae were increased, whereas certain carcinogenic bacteria were overrepresented in the glioma group, including Fusobacterium and Akkermansia. Furthermore, benign and malignant brain tumor patients lacked SCFA-producing probiotics. Thus, a microbial biomarker panel including Fusobacterium, Akkermansia, Escherichia/Shigella, Lachnospira, Agathobacter, and Bifidobacterium was established. Diagnostic models confirmed that this panel could distinguish between brain tumor patients and healthy patients. Additionally, gut microbiota can affect the differentiation and proliferation of brain tumors via several metabolic pathways based on annotations from the Kyoto Encyclopedia of Genes and Genomes (KEGG). This is the first study designed to investigate whether gut microbiota differs between benign and malignant brain tumor patients, and our work concluded that intestinal flora is a valuable tool for the diagnosis and treatment of brain tumors.
    Keywords:  Gut microbiota; biomarker; brain-gut axis; glioma; meningioma; tumors
  9. Cancer Cell. 2022 Mar 14. pii: S1535-6108(22)00068-X. [Epub ahead of print]
      Glioblastomas (GBMs) are aggressive brain tumors characterized by extensive inter- and intratumor heterogeneity. Patient-derived models, such as organoids and explants, have recently emerged as useful models to study such heterogeneity, although the extent to which they can recapitulate GBM genomic features remains unclear. Here, we analyze bulk exome and single-cell genome and transcriptome profiles of 12 IDH wild-type GBMs, including two recurrent tumors, and of patient-derived explants (PDEs) and gliomasphere (GS) lines derived from these tumors. We find that PDEs are genetically similar to, and variably retain gene expression characteristics of, their parent tumors. Notably, PDEs appear to exhibit similar levels of transcriptional heterogeneity compared with their parent tumors, whereas GS lines tend to be enriched for cells in a more uniform transcriptional state. The approaches and datasets introduced here will provide a valuable resource to help guide experiments using GBM-derived models, especially in the context of studying cellular heterogeneity.
    Keywords:  3D models; explant; glioblastoma; gliomasphere; patient-derived models; single-cell RNA-seq; single-cell genome sequencing; single-cell genomics; whole-exome sequencing
  10. Clin Cancer Res. 2022 Mar 16. pii: clincanres.3725.2021. [Epub ahead of print]
      PURPOSE: Despite recent advances in the molecular characterization of gliomas, it remains unclear which patients benefit most from which second line treatments. The TAVAREC trial was a randomized, open-label phase 2 trial assessing the benefit of the addition of the angiogenesis inhibitor bevacizumab to treatment with temozolomide in patients with a first enhancing recurrence of WHO grade 2 or 3 glioma without 1p/19q codeletion. We evaluated the prognostic significance of genome wide DNA methylation profiles and copy number variations on the TAVAREC trial samples.EXPERIMENTAL DESIGN: IDH-mutation status was determined via Sanger sequencing and immunohistochemistry. DNA methylation analysis was performed using the MethylationEPIC BeadChip (Illumina) from which 1p/19q codeletion, MGMT promoter methylation (MGMT-STP27) and homozygous deletion of CDKN2A/B were determined. DNA-methylation classes were determined according to classifiers developed in Heidelberg and TCGA ("Heidelberg" and "TCGA" classifier respectively).
    RESULTS: DNA methylation profiles of 122 samples were successfully determined. As expected, most samples were IDH-mutant (89/122) and MGMT promotor methylated (89/122). Methylation classes were prognostic for time to progression. However, Heidelberg methylation classes determined at time of diagnosis were no longer prognostic following enhancing recurrence of the tumor. In contrast, TCGA methylation classes of primary samples remained prognostic also following enhancing recurrence. Homozygous deletions in CDKN2A/B were found in 10/87 IDH-mutated samples and were prognostically unfavorable at recurrence.
    CONCLUSIONS: DNA methylome Heidelberg classification at time of diagnosis is no longer of prognostic value at the time of enhancing recurrence. CDKN2A/B deletion status was predictive of survival from progression of IDH-mutated tumors.
  11. Brain Tumor Pathol. 2022 Mar 15.
      The relevance of oligodendroglial histological features to patient prognoses is controversial. 93 LrGGs resected for about 2 decades were re-assessed based on WHO2007 with special interest to pure oligodendroglial diagnosis (oligodendroglioma or anaplastic oligodendroglioma) and presence of CFO features. Those histological features, patients OS, and tumor chromosomal/genetic characteristics were correlated each other in each of the 3 IDH-1p/19q-based molecular groups. There was significant association between 1p19q status with the oligodendroglial histological diagnosis as well as presence of CFO in the entire cohort. The oligodendroglial diagnosis was associated with longer OS in IDHmut/codel group; however, this association was not significant in the multivariate analyses. In IDHmut/noncodel and IDH-wildtype groups, the oligodendroglial diagnosis was not associated with patient OS. Presence of CFO was not associated with patient OS in any molecular groups. Gain of 8q was associated with the oligodendroglial diagnosis in IDHmut/noncodel group. Neither the oligodendroglial diagnosis nor CFO was predictive for the methylation status of the MGMT gene in any molecular groups. The oligodendroglial histological features are not independently predictive of either patient prognosis or chemotherapeutic response in LrGGs, leaving the possibility of marginal favorable association only in IDHmut/codel tumors.
    Keywords:  DNA methylation array; Lower-grade glioma; Morphology; Next-generation sequencing; Oligodendroglioma