bims-malgli Biomed News
on Biology of malignant gliomas
Issue of 2020‒09‒13
eleven papers selected by
Oltea Sampetrean
Keio University


  1. Cancers (Basel). 2020 Sep 07. pii: E2534. [Epub ahead of print]12(9):
    Balachandran AA, Larcher LM, Chen S, Veedu RN.
      Brain cancer is one among the rare cancers with high mortality rate that affects both children and adults. The most aggressive form of primary brain tumor is glioblastoma. Secondary brain tumors most commonly metastasize from primary cancers of lung, breast, or melanoma. The five-year survival of primary and secondary brain tumors is 34% and 2.4%, respectively. Owing to poor prognosis, tumor heterogeneity, increased tumor relapse, and resistance to therapies, brain cancers have high mortality and poor survival rates compared to other cancers. Early diagnosis, effective targeted treatments, and improved prognosis have the potential to increase the survival rate of patients with primary and secondary brain malignancies. MicroRNAs (miRNAs) are short noncoding RNAs of approximately 18-22 nucleotides that play a significant role in the regulation of multiple genes. With growing interest in the development of miRNA-based therapeutics, it is crucial to understand the differential role of these miRNAs in the given cancer scenario. This review focuses on the differential expression of ten miRNAs (miR-145, miR-31, miR-451, miR-19a, miR-143, miR-125b, miR-328, miR-210, miR-146a, and miR-126) in glioblastoma and brain metastasis. These miRNAs are highly dysregulated in both primary and metastatic brain tumors, which necessitates a better understanding of their role in these cancers. In the context of the tumor microenvironment and the expression of different genes, these miRNAs possess both oncogenic and/or tumor-suppressive roles within the same cancer.
    Keywords:  brain cancer; cancer metastasis; glioblastoma; glioma; miRNA
    DOI:  https://doi.org/10.3390/cancers12092534
  2. Neurooncol Adv. 2020 Jan-Dec;2(1):2(1): vdaa087
    Smith SJ, Rowlinson J, Estevez-Cebrero M, Onion D, Ritchie A, Clarke P, Wood K, Diksin M, Lourdusamy A, Grundy RG, Rahman R.
      Background: Glioblastoma (GBM) is a highly aggressive brain tumor with rapid subclonal diversification, harboring molecular abnormalities that vary temporospatially, a contributor to therapy resistance. Fluorescence-guided neurosurgical resection utilizes the administration of 5-aminolevulinic acid (5-ALA) generating individually fluorescent tumor cells within a background population of non-neoplastic cells in the invasive tumor region. The aim of the study was to specifically isolate and interrogate the invasive GBM cell population using a novel 5-ALA-based method.Methods: We have isolated the critical invasive GBM cell population by developing 5-ALA-based metabolic fluorescence-activated cell sorting. This allows purification and study of invasive cells from GBM without an overwhelming background "normal brain" signal to confound data. The population was studied using RNAseq, real-time PCR, and immunohistochemistry, with gene targets functionally interrogated on proliferation and migration assays using siRNA knockdown and known drug inhibitors.
    Results: RNAseq analysis identifies specific genes such as SERPINE1 which is highly expressed in invasive GBM cells but at low levels in the surrounding normal brain parenchyma. siRNA knockdown and pharmacological inhibition with specific inhibitors of SERPINE1 reduced the capacity of GBM cells to invade in an in vitro assay. Rodent xenografts of 5-ALA-positive cells were established and serially transplanted, confirming tumorigenicity of the fluorescent patient-derived cells but not the 5-ALA-negative cells.
    Conclusions: Identification of unique molecular features in the invasive GBM population offers hope for developing more efficacious targeted therapies compared to targeting the tumor core and for isolating tumor subpopulations based upon intrinsic metabolic properties.
    Keywords:  5-aminolevulinic acid; gene expression; glioblastoma; heterogeneity; neurosurgery
    DOI:  https://doi.org/10.1093/noajnl/vdaa087
  3. Neurooncol Adv. 2020 Jan-Dec;2(1):2(1): vdaa088
    Jones LE, Hilz S, Grimmer MR, Mazor T, Najac C, Mukherjee J, McKinney A, Chow T, Pieper RO, Ronen SM, Chang SM, Phillips JJ, Costello JF.
      Background: IDH-mutant lower-grade gliomas (LGGs) evolve under the selective pressure of therapy, but well-characterized patient-derived cells (PDCs) modeling evolutionary stages are lacking. IDH-mutant LGGs may develop therapeutic resistance associated with chemotherapy-driven hypermutation and malignant progression. The aim of this study was to establish and characterize PDCs, single-cell-derived PDCs (scPDCs), and xenografts (PDX) of IDH1-mutant recurrences representing distinct stages of tumor evolution.Methods: We derived and validated cell cultures from IDH1-mutant recurrences of astrocytoma and oligodendroglioma. We used exome sequencing and phylogenetic reconstruction to examine the evolutionary stage represented by PDCs, scPDCs, and PDX relative to corresponding spatiotemporal tumor tissue and germline DNA. PDCs were also characterized for growth and tumor immortality phenotypes, and PDX were examined histologically.
    Results: The integrated astrocytoma phylogeny revealed 2 independent founder clonal expansions of hypermutated (HM) cells in tumor tissue that are faithfully represented by independent PDCs. The oligodendroglioma phylogeny showed more than 4000 temozolomide-associated mutations shared among tumor samples, PDCs, scPDCs, and PDX, suggesting a shared monoclonal origin. The PDCs from both subtypes exhibited hallmarks of tumorigenesis, retention of subtype-defining genomic features, production of 2-hydroxyglutarate, and subtype-specific telomere maintenance mechanisms that confer tumor cell immortality. The oligodendroglioma PDCs formed infiltrative intracranial tumors with characteristic histology.
    Conclusions: These PDCs, scPDCs, and PDX are unique and versatile community resources that model the heterogeneous clonal origins and functions of recurrent IDH1-mutant LGGs. The integrated phylogenies advance our knowledge of the complex evolution and immense mutational load of IDH1-mutant HM glioma.
    Keywords:  IDH1-mutant glioma; hypermutation; intracranial xenograft; intratumoral heterogeneity and evolution; patient-derived cells
    DOI:  https://doi.org/10.1093/noajnl/vdaa088
  4. Sci Rep. 2020 Sep 09. 10(1): 14819
    Patel KS, Yao J, Raymond C, Yong W, Everson R, Liau LM, Nathanson D, Kornblum H, Wang C, Oughourlian T, Lai A, Nghiemphu PL, Pope WB, Cloughesy TF, Ellingson BM.
      Previous data suggest that apparent diffusion coefficient (ADC) imaging phenotypes predict survival response to anti-VEGF monotherapy in glioblastoma. However, the mechanism by which imaging may predict clinical response is unknown. We hypothesize that decorin (DCN), a proteoglycan implicated in the modulation of the extracellular microenvironment and sequestration of pro-angiogenic signaling, may connect ADC phenotypes to survival benefit to anti-VEGF therapy. Patients undergoing resection for glioblastoma as well as patients included in The Cancer Genome Atlas (TCGA) and IVY Glioblastoma Atlas Project (IVY GAP) databases had pre-operative imaging analyzed to calculate pre-operative ADCL values, the average ADC in the lower distribution using a double Gaussian mixed model. ADCL values were correlated to available RNA expression from these databases as well as from RNA sequencing from patient derived mouse orthotopic xenograft samples. Targeted biopsies were selected based on ADC values and prospectively collected during resection. Surgical specimens were used to evaluate for DCN RNA and protein expression by ADC value. The IVY Glioblastoma Atlas Project Database was used to evaluate DCN localization and relationship with VEGF pathway via in situ hybridization maps and RNA sequencing data. In a cohort of 35 patients with pre-operative ADC imaging and surgical specimens, DCN RNA expression levels were significantly larger in high ADCL tumors (41.6 vs. 1.5; P = 0.0081). In a cohort of 17 patients with prospectively targeted biopsies there was a positive linear correlation between ADCL levels and DCN protein expression between tumors (Pearson R2 = 0.3977; P = 0.0066) and when evaluating different targets within the same tumor (Pearson R2 = 0.3068; P = 0.0139). In situ hybridization data localized DCN expression to areas of microvascular proliferation and immunohistochemical studies localized DCN protein expression to the tunica adventitia of blood vessels within the tumor. DCN expression positively correlated with VEGFR1 & 2 expression and localized to similar areas of tumor. Increased ADCL on diffusion MR imaging is associated with high DCN expression as well as increased survival with anti-VEGF therapy in glioblastoma. DCN may play an important role linking the imaging features on diffusion MR and anti-VEGF treatment efficacy. DCN may serve as a target for further investigation and modulation of anti-angiogenic therapy in GBM.
    DOI:  https://doi.org/10.1038/s41598-020-71799-w
  5. Cancer Cell. 2020 Aug 31. pii: S1535-6108(20)30419-0. [Epub ahead of print]
    Phillips RE, Soshnev AA, Allis CD.
      Malignant gliomas are central nervous system tumors and remain among the most treatment-resistant cancers. Exome sequencing has revealed significant heterogeneity and important insights into the molecular pathogenesis of gliomas. Mutations in chromatin modifiers-proteins that shape the epigenomic landscape through remodeling and regulation of post-translational modifications on chromatin-are very frequent and often define specific glioma subtypes. This suggests that epigenomic reprogramming may be a fundamental driver of glioma. Here, we describe the key chromatin regulatory pathways disrupted in gliomas, delineating their physiological function and our current understanding of how their dysregulation may contribute to gliomagenesis.
    Keywords:  chromatin; epigenomics; glioma; transcription
    DOI:  https://doi.org/10.1016/j.ccell.2020.08.008
  6. Neuro Oncol. 2020 Sep 08. pii: noaa157. [Epub ahead of print]
    Johnson RM, Phillips HS, Bais C, Brennan CW, Cloughesy TF, Daemen A, Herrlinger U, Jenkins RB, Lai A, Mancao C, Weller M, Wick W, Bourgon R, Garcia J.
      BACKGROUND: We aimed to develop a gene expression-based prognostic signature for isocitrate dehydrogenase (IDH) wild-type glioblastoma using clinical trial datasets representative of glioblastoma clinical trial populations.METHODS: Samples were collected from newly diagnosed patients with IDH wild-type glioblastoma in the ARTE, TAMIGA, EORTC 26101 (referred to as "ATE"), AVAglio, and GLARIUS trials, or treated at UCLA. Transcriptional profiling was achieved with the NanoString gene expression platform. To identify genes prognostic for overall survival (OS), we built an elastic net penalized Cox proportional hazards regression model using the discovery ATE dataset. For validation in independent datasets (AVAglio, GLARIUS, UCLA), we combined elastic net-selected genes into a robust z-score signature (ATE score) to overcome gene expression platform differences between discovery and validation cohorts.
    RESULTS: NanoString data were available from 512 patients in the ATE dataset. Elastic net identified a prognostic signature of 9 genes (CHEK1, GPR17, IGF2BP3, MGMT, MTHFD1L, PTRH2, SOX11, S100A9, and TFRC). Translating weighted elastic net scores to the ATE score conserved the prognostic value of the genes. The ATE score was prognostic for OS in the ATE dataset (P < 0.0001), as expected, and in the validation cohorts (AVAglio, P < 0.0001; GLARIUS, P = 0.02; UCLA, P = 0.004). The ATE score remained prognostic following adjustment for O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation status and corticosteroid use at baseline. A positive correlation between ATE score and proneural/proliferative subtypes was observed in patients with MGMT non-methylated promoter status.
    CONCLUSIONS: The ATE score showed prognostic value and may enable clinical trial stratification for IDH wild-type glioblastoma.
    Keywords:  NanoString; gene expression; glioblastoma; overall survival; prognostic signature
    DOI:  https://doi.org/10.1093/neuonc/noaa157
  7. J Control Release. 2020 Sep 04. pii: S0168-3659(20)30510-1. [Epub ahead of print]
    Cha GD, Kang T, Baik S, Kim D, Choi SH, Hyeon T, Kim DH.
      Glioblastoma multiforme (GBM) is a particularly aggressive and malignant type of brain tumor, notorious for its high recurrence rate and low survival rate. The treatment of GBM is challenging mainly because several issues associated with the GBM microenvironment have not yet been resolved. These obstacles originate from a variety of factors such as genetics, anatomy, and cytology, all of which collectively hinder the treatment of GBM. Recent advances in materials and device engineering have presented new perspectives with regard to unconventional drug administration methods for GBM treatment. Such novel drug delivery approaches, based on the clear understanding of the intrinsic properties of GBM, have shown promise in overcoming some of the obstacles. In this review, we first recapitulate the first-line therapy and clinical challenges in the current treatment of GBM. Afterwards, we introduce the latest technological advances in drug delivery strategies to improve the efficiency for GBM treatment, mainly focusing on materials and devices. We describe such efforts by classifying them into two categories, systemic and local drug delivery. Finally, we discuss unmet challenges and prospects for the clinical translation of these drug delivery technologies.
    Keywords:  Biodegradable implant; Blood-brain barrier; Brain tumor; Drug delivery device; Local drug delivery; Systemic drug delivery
    DOI:  https://doi.org/10.1016/j.jconrel.2020.09.002
  8. Elife. 2020 Sep 10. pii: e52253. [Epub ahead of print]9
    Cui X, Ma C, Vasudevaraja V, Serrano J, Tong J, Peng Y, Delorenzo M, Shen G, Frenster J, Morales RT, Qian W, Tsirigos A, Chi AS, Jain R, Kurz SC, Sulman EP, Placantonakis DG, Snuderl M, Chen W.
      Programmed cell death protein-1 (PD-1) checkpoint immunotherapy efficacy remains unpredictable in glioblastoma (GBM) patients due to the genetic heterogeneity and immunosuppressive tumor microenvironments. Here, we report a microfluidics-based, patient-specific 'GBM-on-a-Chip' microphysiological system to dissect the heterogeneity of immunosuppressive tumor microenvironments and optimize anti-PD-1 immunotherapy for different GBM subtypes. Our clinical and experimental analyses demonstrated that molecularly distinct GBM subtypes have distinct epigenetic and immune signatures that may lead to different immunosuppressive mechanisms. The real-time analysis in GBM-on-a-Chip showed that mesenchymal GBM niche attracted low number of allogeneic CD154+CD8+ T-cells but abundant CD163+ tumor-associated macrophages (TAMs), and expressed elevated PD-1/PD-L1 immune checkpoints and TGF-β1, IL-10, and CSF-1 cytokines compared to proneural GBM. To enhance PD-1 inhibitor nivolumab efficacy, we co-administered a CSF-1R inhibitor BLZ945 to ablate CD163+ M2-TAMs and strengthened CD154+CD8+ T-cell functionality and GBM apoptosis on-chip. Our ex vivo patient-specific GBM-on-a-Chip provides an avenue for a personalized screening of immunotherapies for GBM patients.
    Keywords:  cancer biology; glioblastoma; glioblastoma-on-a-chip; human; immunotherapy; microfluidics; physics of living systems; tumor microenvironment
    DOI:  https://doi.org/10.7554/eLife.52253
  9. Cancers (Basel). 2020 Sep 03. pii: E2511. [Epub ahead of print]12(9):
    Ali MY, Oliva CR, Noman ASM, Allen BG, Goswami PC, Zakharia Y, Monga V, Spitz DR, Buatti JM, Griguer CE.
      Ionizing radiation is a common and effective therapeutic option for the treatment of glioblastoma (GBM). Unfortunately, some GBMs are relatively radioresistant and patients have worse outcomes after radiation treatment. The mechanisms underlying intrinsic radioresistance in GBM has been rigorously investigated over the past several years, but the complex interaction of the cellular molecules and signaling pathways involved in radioresistance remains incompletely defined. A clinically effective radiosensitizer that overcomes radioresistance has yet to be identified. In this review, we discuss the current status of radiation treatment in GBM, including advances in imaging techniques that have facilitated more accurate diagnosis, and the identified mechanisms of GBM radioresistance. In addition, we provide a summary of the candidate GBM radiosensitizers being investigated, including an update of subjects enrolled in clinical trials. Overall, this review highlights the importance of understanding the mechanisms of GBM radioresistance to facilitate the development of effective radiosensitizers.
    Keywords:  glioblastoma; radioresistance; radiosensitizer
    DOI:  https://doi.org/10.3390/cancers12092511
  10. Am J Cancer Res. 2020 ;10(8): 2242-2257
    Zhang C, Jin M, Zhao J, Chen J, Jin W.
      The high mortality and poor clinical prognosis of glioblastoma multiforme (GBM) are concerns for many GBM patients as well as clinicians and researchers. The lack of a preclinical model that can easily be established and accurately recapitulate tumour biology and the tumour microenvironment further complicates GBM research and its clinical translation. GBM organoids (GBOs) are promising high-fidelity models that can be applied to model the disease, develop drugs, establish a living biobank, mimic therapeutic responses and explore personalized therapy. However, GBO models face some challenges, including deficient immune responses, absent vascular system and controversial reliability. In recent years, considerable progress has been achieved in the improvement of brain tumour organoid models and research based on such models. In addition to the traditional cultivation method, these models can be cultivated via genetic engineering and co-culture of cerebral organoids and GBM. In this review, we summarize the applications of GBM organoids and related advances and provide our opinions on associated limitations and challenges.
    Keywords:  Glioblastoma; immunotherapy; invasion; organoids; precision oncology
  11. Cell Syst. 2020 Sep 03. pii: S2405-4712(20)30285-4. [Epub ahead of print]
    Baker GJ, Muhlich JL, Palaniappan SK, Moore JK, Davis SH, Santagata S, Sorger PK.
      Accurately profiling systemic immune responses to cancer initiation and progression is necessary for understanding tumor surveillance and, ultimately, improving therapy. Here, we describe the SYLARAS software tool (systemic lymphoid architecture response assessment) and a dataset collected with SYLARAS that describes the frequencies of immune cells in primary and secondary lymphoid organs and in the tumor microenvironment of mice engrafted with a standard syngeneic glioblastoma (GBM) model. The data resource involves profiles of 5 lymphoid tissues in 48 mice and shows that GBM causes wide-spread changes in the local and systemic immune architecture. We use SYLARAS to identify a subset of CD45R/B220+ CD8+ T cells that is depleted from circulation but accumulates in the tumor mass and confirm this finding using multiplexed immunofluorescence microscopy. SYLARAS is freely available for download at (https://github.com/gjbaker/sylaras). A record of this paper's transparent peer review process is included in the Supplemental Information.
    Keywords:  SYLARAS; computational flow cytometry; glioblastoma; systemic immunoprofiling; systems immunology
    DOI:  https://doi.org/10.1016/j.cels.2020.08.001