bims-malgli Biomed News
on Biology of malignant gliomas
Issue of 2021‒10‒24
eighteen papers selected by
Oltea Sampetrean
Keio University

  1. Front Neurol. 2021 ;12 715206
      Malignant gliomas are highly heterogeneous brain tumors in molecular genetic background. Despite the many recent advances in the understanding of this disease, patients with adult high-grade gliomas retain a notoriously poor prognosis. Fusions involving oncogenes have been reported in gliomas and may serve as novel therapeutic targets to date. Understanding the gene fusions and how they regulate oncogenesis and malignant progression will contribute to explore new approaches for personalized treatment. By now, studies on gene fusions in gliomas remain limited. However, some current clinical trials targeting fusion genes have presented exciting preliminary findings. The aim of this review is to summarize all the reported fusion genes in high-grade gliomas so far, discuss the characterization of some of the most popular gene fusions occurring in malignant gliomas, as well as their function in tumorigenesis, and the underlying clinical implication as therapeutic targets.
    Keywords:  fusion gene; glioblastoma; high-grade glioma; personalized cancer medicine; targeted therapy
  2. Apoptosis. 2021 Oct 23.
      Around three out of one hundred thousand people are diagnosed with glioblastoma multiforme, simply called glioblastoma, which is the most common primary brain tumor in adults. With a dismal prognosis of a little over a year, receiving a glioblastoma diagnosis is oftentimes fatal. A major advancement in its treatment was made almost two decades ago when the alkylating chemotherapeutic agent temozolomide (TMZ) was combined with radiotherapy (RT). Little progress has been made since then. Therapies that focus on the modulation of autophagy, a key process that regulates cellular homeostasis, have been developed to curb the progression of glioblastoma. The dual role of autophagy (cell survival or cell death) in glioblastoma has led to the development of autophagy inhibitors and promoters that either work as monotherapies or as part of a combination therapy to induce cell death, cellular senescence, and counteract the ability of glioblastoma stem cells (GSCs) for initiating tumor recurrence. The myriad of cellular pathways that act upon the modulation of autophagy have created contention between two groups: those who use autophagy inhibition versus those who use promotion of autophagy to control glioblastoma growth. We discuss rationale for using current major therapeutics, their molecular mechanisms for modulation of autophagy in glioblastoma and GSCs, their potentials for making strides in combating glioblastoma progression, and their possible shortcomings. These shortcomings may fuel the innovation of novel delivery systems and therapies involving TMZ in conjunction with another agent to pave the way towards a new gold standard of glioblastoma treatment.
    Keywords:  Apoptosis; Autophagy inhibition; Autophagy promotion; Combination therapy option; Glioblastoma; Monotherapy option
  3. Cancer Metastasis Rev. 2021 Oct 23.
      In patients with glioblastoma, the average survival time with current treatments is short, mainly due to recurrences and resistance to therapy. This insufficient treatment success is, in large parts, due to the tremendous molecular heterogeneity of gliomas, which affects the overall prognosis and response to therapies and plays a vital role in gliomas' grading. In addition, the tumor microenvironment is a major player for glioma development and resistance to therapy. Active communication between glioma cells and local or neighboring healthy cells and the immune environment promotes the cancerogenic processes and contributes to establishing glioma stem cells, which drives therapy resistance. Besides genetic alterations in the primary tumor, tumor-released factors, cytokines, proteins, extracellular vesicles, and environmental influences like hypoxia provide tumor cells the ability to evade host tumor surveillance machinery and promote disease progression. Moreover, there is increasing evidence that these players affect the molecular biological properties of gliomas and enable inter-cell communication that supports pro-cancerogenic cell properties. Identifying and characterizing these complex mechanisms are inevitably necessary to adapt therapeutic strategies and to develop novel measures. Here we provide an update about these junctions where constant traffic of biomolecules adds complexity in the management of glioblastoma.
    Keywords:  Cancer microenvironment; Cancer stem cells; Glioblastoma; Glioma; Stem cells; Tumor microenvironment
  4. Neuro Oncol. 2021 Oct 17. pii: noab244. [Epub ahead of print]
      BACKGROUND: Glioblastoma (GBM) remains a largely incurable disease as current therapy fails to target the invasive nature of GBM growth in disease progression and recurrence. Here we use the FDA-approved drug and small molecule Hippo inhibitor Verteporfin to target YAP-TEAD activity, known to mediate convergent aspects of tumor invasion/metastasis, and assess the drug's efficacy and survival benefit in GBM models.METHODS: Up to eight low-passage patient-derived GBM cell lines with distinct genomic drivers, including three primary/recurrent pairs, were treated with Verteporfin or vehicle to assess in-vitro effects on proliferation, migration, YAP-TEAD activity, and transcriptomics. Patient-derived orthotopic xenograft models (PDX) were used to assess Verteporfin's brain penetrance and effects on tumor burden and survival.
    RESULTS: Verteporfin treatment disturbed YAP/TAZ-TEAD activity; disrupted transcriptome signatures related to invasion, epithelial-to-mesenchymal, and proneural-to-mesenchymal transition, phenocopying TEAD1-knockout effects; and impaired tumor migration/invasion dynamics across primary and recurrent GBM lines. In an aggressive orthotopic PDX GBM model, short-term Verteporfin treatment consistently diminished core and infiltrative tumor burden, which was associated with decreased tumor expression of Ki67, nuclear YAP, TEAD1, and TEAD-associated targets EGFR, CDH2 and ITGB1. Finally, long-term Verteporfin treatment appeared non-toxic and conferred survival benefit compared to vehicle in two PDX models: as monotherapy in primary (de-novo) GBM and in combination with Temozolomide chemoradiation in recurrent GBM, where VP treatment associated with increased MGMT methylation.
    CONCLUSIONS: We demonstrate combined anti-invasive and anti-proliferative efficacy for Verteporfin with survival benefit in preclinical GBM models, indicating potential therapeutic value of this already FDA-approved drug if repurposed for glioblastoma patients.
    Keywords:  Verteporfin; YAP-TEAD; invasion; migration; preclinical
  5. Neuromolecular Med. 2021 Oct 22.
      Malignant brain tumors are among the most intractable cancers, including malignancies such as glioblastoma, diffuse midline glioma, medulloblastoma, and ependymoma. Unfortunately, treatment options for these brain tumors have been inadequate and complex, leading to poor prognoses and creating a need for new treatment modalities. Aberrant epigenetics define these types of tumors, with underlying changes in DNA methylation, histone modifications, chromatin structure and noncoding RNAs. Epigenetic-targeted therapies are an alternative that have the potential to reverse the epigenetic deregulation underpinning brain malignancies. Various drugs targeting epigenetic regulators have shown promise in preclinical and clinical testing. In this review, we highlight some of the recent emerging epigenetic targeted therapies for brain tumors being evaluated in the discovery phase and in clinical trials.
    Keywords:  Brain tumors; Clinical trials; Epigenetic; Mechanisms
  6. Cancers (Basel). 2021 Oct 14. pii: 5157. [Epub ahead of print]13(20):
      (1) Background: Glioblastoma is the most common malignant brain tumor in adults. Its etiology remains unknown in most cases. Glioblastoma pathogenesis consists of a progressive infiltration of the white matter by tumoral cells leading to progressive neurological deficit, epilepsy, and/or intracranial hypertension. The mean survival is between 15 to 17 months. Given this aggressive prognosis, there is an urgent need for a better understanding of the underlying mechanisms of glioblastoma to unveil new diagnostic strategies and therapeutic targets through a deeper understanding of its biology. (2) Methods: To systematically address this issue, we performed targeted and untargeted metabolomics-based investigations on both tissue and plasma samples from patients with glioblastoma. (3) Results: This study revealed 176 differentially expressed lipids and metabolites, 148 in plasma and 28 in tissue samples. Main biochemical classes include phospholipids, acylcarnitines, sphingomyelins, and triacylglycerols. Functional analyses revealed deep metabolic remodeling in glioblastoma lipids and energy substrates, which unveils the major role of lipids in tumor progression by modulating its own environment. (4) Conclusions: Overall, our study demonstrates in situ and systemic metabolic rewiring in glioblastoma that could shed light on its underlying biological plasticity and progression to inform diagnosis and/or therapeutic strategies.
    Keywords:  brain tumor; glioblastoma; high-grade glioma; machine learning; mass spectrometry; metabolomics; neuro-oncology; omics
  7. Neurooncol Adv. 2021 Jan-Dec;3(1):3(1): vdab127
      Background: Glioblastoma remains a deadly brain cancer with dismal prognosis. Genetic alterations, including IDH mutations, 1p19q co-deletion status and MGMT promoter methylation have been proven to be prognostic and predictive to response to treatment in gliomas. In this manuscript, we aimed to correlate other mutations and genetic alterations with various clinical endpoints in patients with IDH-wild-type (IDHwt) glioblastoma.Methods: We compiled a comprehensive clinically annotated database of IDHwt GBM patients treated at the Ohio State University Wexner Medical Center for whom we had mutational data through a CLIA-certified genomic laboratory. We then added data that is publicly available from Memorial Sloan Kettering Cancer Center through cBioPortal. Each of the genetic alterations (mutations, deletions, and amplifications) served as a variable in univariate and multivariate Cox proportional hazard models.
    Results: A total of 175 IDHwt GBM patients with available MGMT promoter methylation data from both cohorts were included in the analysis. As expected, MGMT promoter methylation was significantly associated with improved overall survival (OS). Median OS for MGMT promoter methylated and unmethylated GBM was 26.5 and 18 months, respectively (HR 0.45; P = .003). Moreover, EGFR/ERBB alterations were associated with favorable outcome (HR of 0.37 (P = .003), but only in MGMT promoter unmethylated GBM. We further found that patients with EGFR/ERBB alterations who also harbored PDGFRA amplification had a significantly worse outcome (HR 7.89; P = .025).
    Conclusions: Our data provide further insight into the impact of genetic alterations on various clinical outcomes in IDHwt GBM in 2 cohorts of patients with detailed clinical information and inspire new therapeutic strategies for IDHwt GBM.
    Keywords:  EGFR; GBM; IDH; MGMT; PDGFR; next-generation sequencing
  8. Molecules. 2021 Oct 12. pii: 6146. [Epub ahead of print]26(20):
      Gliomas are the most common malignant brain tumors in adults, characterized by a high proliferation and invasion. The tumor microenvironment is rich in growth-promoting signals and immunomodulatory pathways, which increase the tumor's aggressiveness. In response to hypoxia and glioma therapy, the amounts of adenosine triphosphate (ATP) and adenosine diphosphate (ADP) strongly increase in the extracellular space, and the purinergic signaling is triggered by nucleotides' interaction in P2 receptors. Several cell types are present in the tumor microenvironment and can facilitate tumor growth. In fact, tumor cells can activate platelets by the ADP-P2Y12 engagement, which plays an essential role in the cancer context, protecting tumors from the immune attack and providing molecules that contribute to the growth and maintenance of a rich environment to sustain the protumor cycle. Besides platelets, the P2Y12 receptor is expressed by some tumors, such as renal carcinoma, colon carcinoma, and gliomas, being related to tumor progression. In this context, this review aims to depict the glioma microenvironment, focusing on the relationship between platelets and tumor malignancy.
    Keywords:  P2Y12; glioma; platelets; purinergic signaling; tumor microenvironment
  9. Cells. 2021 Oct 01. pii: 2621. [Epub ahead of print]10(10):
      Rapid diagnosis and therapeutic monitoring of aggressive diseases such as glioblastoma can improve patient survival by providing physicians the time to optimally deliver treatment. This research tested whether metabolic imaging with hyperpolarized MRI could detect changes in tumor progression faster than conventional anatomic MRI in patient-derived glioblastoma murine models. To capture the dynamic nature of cancer metabolism, hyperpolarized MRI, NMR spectroscopy, and immunohistochemistry were performed at several time-points during tumor development, regression, and recurrence. Hyperpolarized MRI detected significant changes of metabolism throughout tumor progression whereas conventional MRI was less sensitive. This was accompanied by aberrations in amino acid and phospholipid lipid metabolism and MCT1 expression. Hyperpolarized MRI can help address clinical challenges such as identifying malignant disease prior to aggressive growth, differentiating pseudoprogression from true progression, and predicting relapse. The individual evolution of these metabolic assays as well as their correlations with one another provides context for further academic research.
    Keywords:  glioblastoma; hyperpolarization; magnetic resonance imaging; metabolism; nuclear magnetic resonance; radiation therapy; tumor development; tumor recurrence; tumor regression
  10. Cell Rep. 2021 Oct 19. pii: S2211-1247(21)01340-1. [Epub ahead of print]37(3): 109873
      Long non-coding RNAs (lncRNAs) are increasingly recognized as functional units in cancer and powerful biomarkers; however, most remain uncharacterized. Here, we analyze 5,592 prognostic lncRNAs in 9,446 cancers of 30 types using machine learning. We identify 166 lncRNAs whose expression correlates with survival and improves the accuracy of common clinical variables, molecular features, and cancer subtypes. Prognostic lncRNAs are often characterized by switch-like expression patterns. In low-grade gliomas, HOXA10-AS activation is a robust marker of poor prognosis that complements IDH1/2 mutations, as validated in another retrospective cohort, and correlates with developmental pathways in tumor transcriptomes. Loss- and gain-of-function studies in patient-derived glioma cells, organoids, and xenograft models identify HOXA10-AS as a potent onco-lncRNA that regulates cell proliferation, contact inhibition, invasion, Hippo signaling, and mitotic and neuro-developmental pathways. Our study underscores the pan-cancer potential of the non-coding transcriptome for identifying biomarkers and regulators of cancer progression.
    Keywords:  HOXA10-AS; Hippo signalling; cancer; cancer driver genes; glioblastoma; glioma; lncRNAs; long non-coding RNAs; machine learning; prognostic biomarkers
  11. Cancer Res. 2021 Oct 20. pii: canres.1456.2021. [Epub ahead of print]
      The dynamic changes of RNA N6-methyl-adenosine (m6A) during cancer progression contribute to quick adaption to microenvironmental changes. Here, we profiled the cancer cell m6A dynamics in the hypoxic tumor niche and its pathological consequences in glioblastoma multiforme (GBM). The m6A demethylase ALKBH5 was induced in GBM models under hypoxic conditions and was associated with a hypoxic gene signature in GBM patient samples. Depletion or inactivation of ALKBH5 in GBM cells significantly suppressed hypoxia-induced tumor-associated macrophage (TAM) recruitment and immunosuppression in allograft tumors. Expression and secretion of CXCL8/IL8 was significantly suppressed in ALKBH5-deficient tumors. However, ALKBH5 did not regulate CXCL8 m6A directly. Instead, hypoxia-induced ALKBH5 erased m6A deposition from the lncRNA NEAT1, stabilizing the transcript and facilitating NEAT1-mediated paraspeckle assembly, which led to relocation of the transcriptional repressor SFPQ from the CXCL8 promoter to paraspeckles and, ultimately, upregulation of CXCL8/IL8 expression. Accordingly, ectopic expression of CXCL8 in ALKBH5-deficient GBM cells partially restored TAM recruitment and tumor progression. Together, this study links hypoxia-induced epitranscriptomic changes to the emergence of an immunosuppressive microenvironment facilitating tumor evasion.
  12. Annu Rev Med. 2021 Oct 19.
      Faced with unique immunobiology and marked heterogeneity, treatment strategies for glioblastoma require therapeutic approaches that diverge from conventional oncological strategies. The selection and prioritization of targeted and immunotherapeutic strategies will need to carefully consider these features and companion biomarkers developed alongside treatment strategies to identify the appropriate patient populations. Novel clinical trial strategies that interrogate the tumor microenvironment for drug penetration and target engagement will inform go/no-go later-stage clinical studies. Innovative trial designs and analyses are needed to move effective agents toward regulatory approvals more rapidly. Expected final online publication date for the Annual Review of Medicine, Volume 73 is January 2022. Please see for revised estimates.
  13. Cells. 2021 Oct 01. pii: 2625. [Epub ahead of print]10(10):
      Glioblastoma (GBM) is the most malignant tumor in the brain. In addition to the vascular pattern with thin-walled vessels and findings of sprouting angiogenesis, GBM presents a bizarre microvasculature (BM) formed by vascular clusters, vascular garlands, and glomeruloid bodies. The mechanisms in BM morphogenesis are not well known. Our objective was to assess the role of pericyte/endothelial proliferation and intussusceptive angiogenic mechanisms in the formation of the BM. For this purpose, we studied specimens of 66 GBM cases using immunochemistry and confocal microscopy. In the BM, the results showed (a) transitional forms between the BM patterns, mostly with prominent pericytes covering all the abluminal endothelial cell (EC) surface of the vessels, (b) a proliferation index high in the prominent pericytes and low in ECs (47.85 times higher in pericytes than in ECs), (c) intravascular pillars (hallmark of intussusceptive angiogenesis) formed by transcapillary interendothelial bridges, endothelial contacts of opposite vessel walls, and vessel loops, and (d) the persistence of these findings in complex glomeruloid bodies. In conclusion, disproportion in pericyte/EC proliferation and mechanisms of intussusceptive angiogenesis participate in BM formation. The contributions have morphogenic and clinical interest since pericytes and intussusceptive angiogenesis can condition antiangiogenic therapy in GBM.
    Keywords:  bizarre/aberrant microvasculature; endothelial cells; glioblastoma; glomeruloid bodies; intussusceptive angiogenesis; pericytes; proliferation index
  14. Nat Commun. 2021 Oct 21. 12(1): 6130
      Epigenetic mechanisms which play an essential role in normal developmental processes, such as self-renewal and fate specification of neural stem cells (NSC) are also responsible for some of the changes in the glioblastoma (GBM) genome. Here we develop a strategy to compare the epigenetic and transcriptional make-up of primary GBM cells (GIC) with patient-matched expanded potential stem cell (EPSC)-derived NSC (iNSC). Using a comparative analysis of the transcriptome of syngeneic GIC/iNSC pairs, we identify a glycosaminoglycan (GAG)-mediated mechanism of recruitment of regulatory T cells (Tregs) in GBM. Integrated analysis of the transcriptome and DNA methylome of GBM cells identifies druggable target genes and patient-specific prediction of drug response in primary GIC cultures, which is validated in 3D and in vivo models. Taken together, we provide a proof of principle that this experimental pipeline has the potential to identify patient-specific disease mechanisms and druggable targets in GBM.
  15. Biosensors (Basel). 2021 Oct 13. pii: 388. [Epub ahead of print]11(10):
      Glioblastoma (GBM) is one of the most aggressive solid tumors, particularly due to the presence of cancer stem cells (CSCs). Nowadays, the characterization of this cell type with an efficient, fast and low-cost method remains an issue. Hence, we have developed a microfluidic lab-on-a-chip based on dielectrophoresis (DEP) single cell electro-manipulation to measure the two crossover frequencies: fx01 in the low-frequency range (below 500 kHz) and fx02 in the ultra-high-frequency range (UHF, above 50 MHz). First, in vitro conditions were investigated. An U87-MG cell line was cultured in different conditions in order to induce an undifferentiated phenotype. Then, ex vivo GBM cells from patients' primary cell culture were passed through the developed microfluidic system and characterized in order to reflect clinical conditions. This article demonstrates that the usual exploitation of low-frequency range DEP does not allow the discrimination of the undifferentiated GBM cells from the differentiated one. However, the presented study highlights the use of UHF-DEP as a relevant discriminant parameter. The proposed microfluidic lab-on-a-chip is able to follow the kinetics of U87-MG phenotype transformation in a CSC enrichment medium and the cancer stem cells phenotype acquirement.
    Keywords:  cancer stem cells; glioblastoma cells; high-frequency dielectrophoresis; microfluidic point-of-care device; single cell manipulation
  16. Biomedicines. 2021 Sep 28. pii: 1343. [Epub ahead of print]9(10):
      Nuclear lamina components have long been regarded as scaffolding proteins, forming a dense fibrillar structure necessary for the maintenance of the nucleus shape in all the animal kingdom. More recently, mutations, aberrant localisation and deregulation of these proteins have been linked to several diseases, including cancer. Using publicly available data we found that the increased expression levels of the nuclear protein Lamin A/C correlate with a reduced overall survival in The Cancer Genome Atlas Research Network (TCGA) patients affected by glioblastoma multiforme (GBM). We show that the expression of the LMNA gene is linked to the enrichment of cancer-related pathways, particularly pathways related to cell adhesion and cell migration. Mimicking the modulation of LMNA in a GBM preclinical cancer model, we confirmed both in vitro and in vivo that the increased expression of LMNA is associated with an increased aggressiveness and tumorigenicity. In addition, delving into the possible mechanism behind LMNA-induced GBM aggressiveness and tumorigenicity, we found that the mTORC2 component, Rictor, plays a central role in mediating these effects.
    Keywords:  Lamin A/C; Rictor; glioblastoma
  17. Metabolites. 2021 Sep 29. pii: 668. [Epub ahead of print]11(10):
      The tumor microenvironment is a critical regulator of cancer development and progression as well as treatment response and resistance in brain neoplasms. The available techniques for investigation, however, are not well suited for noninvasive in vivo characterization in humans. A total of 120 patients (59 females; 61 males) with newly diagnosed contrast-enhancing brain tumors (64 glioblastoma, 20 brain metastases, 15 primary central nervous system (CNS) lymphomas (PCNSLs), and 21 meningiomas) were examined with a previously established physiological MRI protocol including quantitative blood-oxygen-level-dependent imaging and vascular architecture mapping. Six MRI biomarker maps for oxygen metabolism and neovascularization were fused for classification of five different tumor microenvironments: glycolysis, oxidative phosphorylation (OxPhos), hypoxia with/without neovascularization, and necrosis. Glioblastoma showed the highest metabolic heterogeneity followed by brain metastasis with a glycolysis-to-OxPhos ratio of approximately 2:1 in both tumor entities. In addition, glioblastoma revealed a significant higher percentage of hypoxia (24%) compared to all three other brain tumor entities: brain metastasis (7%; p < 0.001), PCNSL (8%; p = 0.001), and meningioma (8%; p = 0.003). A more aggressive biological brain tumor behavior was associated with a higher percentage of hypoxia and necrosis and a lower percentage of remaining vital tumor tissue and aerobic glycolysis. The proportion of oxidative phosphorylation, however, was rather similar (17-26%) for all four brain tumor entities. Tumor microenvironment (TME) mapping provides insights into neurobiological differences of contrast-enhancing brain tumors and deserves further clinical cancer research attention. Although there is a long roadmap ahead, TME mapping may become useful in order to develop new diagnostic and therapeutic approaches.
    Keywords:  brain tumors; energy metabolism; hypoxia; metabolic imaging; neovascularization; physiological MRI; tumor microenvironment
  18. Molecules. 2021 Oct 10. pii: 6112. [Epub ahead of print]26(20):
      Alterations in the carnitine shuttle system may be an indication of the presence of cancer. As such, in-depth analyses of this pathway in different malignant tumors could be important for the detection and treatment of this disease. The current study aims to assess the profiles of carnitine and acylcarnitines in gliomas with respect to their grade, the presence of isocitrate dehydrogenase (IDH) mutations, and 1p/19q co-deletion. Brain tumors obtained from 19 patients were sampled on-site using solid-phase microextraction (SPME) immediately following excision. Analytes were desorbed and then analyzed via liquid chromatography-high-resolution mass spectrometry. The results showed that SPME enabled the extraction of carnitine and 22 acylcarnitines. An analysis of the correlation factor revealed the presence of two separate clusters: short-chain and long-chain carnitine esters. Slightly higher carnitine and acylcarnitine concentrations were observed in the higher-malignancy tumor samples (high vs. low grade) and in those samples with worse projected clinical outcomes (without vs. with IDH mutation; without vs. with 1p/19q co-deletion). Thus, the proposed chemical biopsy approach offers a simple solution for on-site sampling that enables sample preservation, thus supporting comprehensive multi-method analyses.
    Keywords:  acylcarnitine; cancer; carnitine; glioma; liquid chromatography–mass spectrometry LC–MS; solid-phase microextraction SPME