bims-malgli Biomed News
on Biology of malignant gliomas
Issue of 2022‒08‒28
seventeen papers selected by
Oltea Sampetrean
Keio University
  1. National-level overall survival patterns for molecularly-defined diffuse glioma types in the United States.
  2. CD44 expressed by myeloid cells promotes glioma invasion.
  3. A protocol to use Drosophila melanogaster larvae to model human glioblastoma.
  4. The effect of dexamethasone on the microenvironment and efficacy of checkpoint inhibitors in glioblastoma: a systematic review.
  5. Effect of Expression of Nuclear-Encoded Cytochrome C Oxidase Subunit 4 Isoforms on Metabolic Profiles of Glioma Cells.
  6. Abrogation of Cellular Senescence Induced by Temozolomide in Glioblastoma Cells: Search for Senolytics.
  7. Superinduction of immunosuppressive glioblastoma extracellular vesicles by IFN-γ through PD-L1 and IDO1.
  8. World Health Organization 2021 Classification of Central Nervous System Tumors and Implications for Therapy for Adult-Type Gliomas: A Review.
  9. Targeting the Sphingolipid Rheostat in Gliomas.
  10. Lipid Metabolism in Glioblastoma: From De Novo Synthesis to Storage.
  11. An affinity for brainstem microglia in pediatric high-grade gliomas of brainstem origin.
  12. Targeting HOTAIRM1 ameliorates glioblastoma by disrupting mitochondrial oxidative phosphorylation and serine metabolism.
  13. A novel quinoline-based fluorescent probe for real-time monitoring of Cys in glioma.
  14. Prognostic risk stratification of gliomas using deep learning in digital pathology images.
  15. Protocol to analyze antitumor immunity of orthotopic injection and spontaneous murine high-grade glioma models using flow cytometry and single-cell RNA sequencing.
  16. Current understanding of the human microbiome in glioma.
  17. Aerobic glycolysis promotes tumor immune evasion by hexokinase2-mediated phosphorylation of IκBα.
  1. Neuro Oncol. 2022 Aug 22. pii: noac198. [Epub ahead of print]
    National-level overall survival patterns for molecularly-defined diffuse glioma types in the United States.
    Quinn T Ostrom, Madison L Shoaf, Gino Cioffi, Kristin Waite, Carol Kruchko, Patrick Y Wen, Daniel Brat, Jill S Barnholtz-Sloan, J Bryan Iorgulescu.
      BACKGROUND: Molecularly-defined diffuse glioma types - including IDH-wildtype glioblastoma, IDH-mutant astrocytoma, IDH-mutant 1p/19q-codeleted oligodendroglioma, and H3 K27M-mutant diffuse midline glioma - were incorporated into U.S. cancer registry reporting for individuals with brain tumors beginning in 2018. We leveraged these new data to estimate the national-level overall survival (OS) patterns associated with glioma integrated diagnoses.METHODS: Individuals diagnosed with diffuse gliomas in 2018 and had brain molecular marker data were identified within the U.S. National Cancer Database. OS was estimated using Kaplan Meier methods and stratified by WHO CNS grade, age, sex, tumor size, treatment, extent of resection, and MGMT promoter methylation. Additionally, the effects of WHO CNS grade were examined among individuals with IDH-wildtype astrocytic gliomas.
    RESULTS: 8,651 individuals were identified. One-year OS was 53.7% for WHO grade 4 IDH-wildtype glioblastomas; 98.0%, 92.4%, and 76.3% for WHO grade 2, 3, and 4 IDH-mutant astrocytomas, respectively; 97.9% and 94.4% for WHO grade 2 and 3 IDH-mutant 1p/19q-codeleted oligodendrogliomas, respectively; and 55.9% for H3 K27M-mutant diffuse midline gliomas. Among IDH-wildtype glioblastomas, median OS was 17.1 months and 12.4 months for methylated and unmethylated MGMT promoters. Additionally, IDH-wildtype diffuse astrocytic gliomas reported as WHO grade 2 or 3 demonstrated longer OS compared to grade 4 tumors (both p<0.001).
    CONCLUSIONS: Our findings provide the initial national OS estimates for molecularly-defined diffuse gliomas in the U.S. and illustrate the importance of incorporating such data into cancer registry reporting.
    Keywords:  Diffuse glioma; Glioblastoma; IDH mutation; MGMT promoter methylation; Survival
    DOI:  https://doi.org/10.1093/neuonc/noac198
  2. Front Oncol. 2022 ;12 969787
    CD44 expressed by myeloid cells promotes glioma invasion.
    Ekaterina L Ivanova, Barbara Costa, Tanja Eisemann, Sabrina Lohr, Pavle Boskovic, Viktoria Eichwald, Jasmin Meckler, Manfred Jugold, Veronique Orian-Rousseau, Heike Peterziel, Peter Angel.
      Glioblastoma multiforme (GBM) is one of the most common and malignant brain tumors in adulthood with a median survival of only 15 months. This poor prognosis is related to GBM's ability to extensively infiltrate the surrounding brain parenchyma resulting in diffuse spread of neoplastic cells in the brain, responsible for high rate of recurrence. CD44 (Cluster of Differentiation 44) is a transmembrane protein, overexpressed in multiple cancer types, including gliomas, and implicated in cell motility, proliferation and angiogenesis. Multiple studies have investigated the role of CD44 in GBM cells and have highlighted a link between tumor malignancy and CD44 expression. However up to date, little is known of the role of CD44 on cells from the tumor microenvironment (TME). Here, we have investigated a potential role of CD44 in the TME in regards to GBM invasiveness. Using an ex-vivo organotypic brain slice invasion assay, we show that absence of CD44 from the TME impairs the ability of glioma cells to invade the surrounding brain parenchyma. By deleting CD44 in the astrocytic, endothelial and myeloid compartments, we show that it is specifically CD44 expression in myeloid cells that is responsible for the observed phenotype. Combining in vivo studies in cell-specific knock-out mice and in vitro analyses on primary microglia we demonstrate that myeloid CD44 is implicated in Toll Like Receptor 2 signaling and is a major regulator of Matrix metalloproteinase 9 expression.
    Keywords:  CD44; MMP9; TLR2; glioblastoma; microglia; tumor microenvironment
    DOI:  https://doi.org/10.3389/fonc.2022.969787
  3. STAR Protoc. 2022 Sep 16. 3(3): 101609
    A protocol to use Drosophila melanogaster larvae to model human glioblastoma.
    Julia G Saborio, Elizabeth E Young, Alexander S Chen, Renee D Read.
      This protocol describes a genetic model system we developed for glioblastoma (GBM) in Drosophila melanogaster, which can be used to explore the pathogenic phenotypic effects of mutated genetic pathways and to identify potential therapeutic targets for tumors with these mutations. We present genetic schemes and experimental steps needed to create neoplastic glial brain tumors in larval Drosophila. We also provide steps to manipulate genes in this model and to perform brain fixation, immunostaining, and imaging of neoplastic larval brains. For complete details on the use and execution of this protocol, please refer to Read et al., (2009).
    Keywords:  Cancer; Developmental biology; Genetics; Model organisms
    DOI:  https://doi.org/10.1016/j.xpro.2022.101609
  4. Neurooncol Adv. 2022 Jan-Dec;4(1):4(1): vdac087
    The effect of dexamethasone on the microenvironment and efficacy of checkpoint inhibitors in glioblastoma: a systematic review.
    Kyra X Swildens, Peter A E Sillevis Smitt, Martin J van den Bent, Pim J French, Marjolein Geurts.
      Background: Checkpoint inhibitor immunotherapy has not proven clinically effective in glioblastoma. This lack of effectiveness may be partially attributable to the frequent administration of dexamethasone in glioblastoma patients. In this systematic review, we assess whether dexamethasone (1) affects the glioblastoma microenvironment and (2) interferes with checkpoint inhibitor immunotherapy efficacy in the treatment of glioblastoma.Methods: PubMed and Embase were systematically searched for eligible articles published up to September 15, 2021. Both in vitro and in vivo preclinical studies, as well as clinical studies were selected. The following information was extracted from each study: tumor model, corticosteroid treatment, and effects on individual immune components or checkpoint inhibitor immunotherapy.
    Results: Twenty-one preclinical studies in cellular glioma models (n = 10), animal glioma models (n = 6), and glioblastoma patient samples (n = 7), and 3 clinical studies were included. Preclinical studies show that dexamethasone decreases the presence of microglia and other macrophages as well as the number of T lymphocytes in both tumor tissue and periphery. Dexamethasone abrogates the antitumor effects of checkpoint inhibitors on T lymphocytes in preclinical studies. Although randomized studies directly addressing our research question are lacking, clinical studies suggest a negative association between corticosteroids and survival outcomes in glioblastoma patients receiving checkpoint inhibitors after adjustment for relevant prognostic factors.
    Conclusions: Preclinical research shows that dexamethasone inhibits the antitumor immune response in glioma, thereby promoting a protumorigenic microenvironment. The efficacy of checkpoint inhibitor immunotherapy in glioblastoma patients may therefore be negatively affected by the use of dexamethasone. Future research could investigate the potential of edema-reducing alternatives to dexamethasone.
    Keywords:  checkpoint inhibitors; corticosteroids; dexamethasone; glioblastoma; immunotherapy
    DOI:  https://doi.org/10.1093/noajnl/vdac087
  5. Metabolites. 2022 Aug 16. pii: 748. [Epub ahead of print]12(8):
    Effect of Expression of Nuclear-Encoded Cytochrome C Oxidase Subunit 4 Isoforms on Metabolic Profiles of Glioma Cells.
    Claudia R Oliva, Md Yousuf Ali, Susanne Flor, Corinne E Griguer.
      Although often effective at treating newly diagnosed glioblastoma (GBM), increasing evidence suggests that chemo- and radiotherapy-induced alterations in tumor metabolism promote GBM recurrence and aggressiveness, as well as treatment resistance. Recent studies have demonstrated that alterations in glioma cell metabolism, induced by a switch in the isoform expression of cytochrome c oxidase subunit 4 (COX4), a key regulatory subunit of mammalian cytochrome c oxidase, could promote these effects. To understand how the two COX4 isoforms (COX4-1 and COX4-2) differentially affect glioma metabolism, glioma samples harvested from COX4-1- or COX4-2-overexpressing U251 cells were profiled using Gas chromatography-mass spectrometry GC-MS and Liquid Chromatography - Tandem Mass Spectrometry LC-MS/MS metabolomics platforms. The concentration of 362 metabolites differed significantly in the two cell types. The two most significantly upregulated pathways associated with COX4-1 overexpression were purine and glutathione metabolism; the two most significantly downregulated metabolic pathways associated with COX4-1 expression were glycolysis and fatty acid metabolism. Our study provides new insights into how Cytochrome c oxidase (CcO) regulatory subunits affect cellular metabolic networks in GBM and identifies potential targets that may be exploited for therapeutic benefit.
    Keywords:  COX4-1; cytochrome c oxidase; glioma; metabolomics
    DOI:  https://doi.org/10.3390/metabo12080748
  6. Cells. 2022 Aug 19. pii: 2588. [Epub ahead of print]11(16):
    Abrogation of Cellular Senescence Induced by Temozolomide in Glioblastoma Cells: Search for Senolytics.
    Lea Beltzig, Markus Christmann, Bernd Kaina.
      A first-line therapeutic for high-grade glioma, notably glioblastoma (GBM), is the DNA methylating drug temozolomide (TMZ). Previously, we showed that TMZ induces not only apoptosis and autophagy, but also cellular senescence (CSEN). We presented the hypothesis that GBM cells may escape from CSEN, giving rise to recurrent tumors. Furthermore, the inflammatory phenotype associated with CSEN may attenuate chemotherapy and drive tumor progression. Therefore, treatments that specifically target senescent cells, i.e., senolytic drugs, may lead to a better outcome of GBM therapy by preventing recurrences and tumor inflammation. Here, we tested Bcl-2 targeting drugs including ABT-737, ABT-263 (navitoclax), several natural substances such as artesunate, fisetin and curcumin as well as lomustine (CCNU) and ionizing radiation (IR) for their senolytic capacity in GBM cells. Additionally, several proteins involved in the DNA damage response (DDR), ATM, ATR, Chk1/2, p53, p21, NF-kB, Rad51, PARP, IAPs and autophagy, a pathway involved in CSEN induction, were tested for their impact in maintaining CSEN. Treatment of GBM cells with a low dose of TMZ for 8-10 days resulted in &gt;80% CSEN, confirming CSEN to be the major trait induced by TMZ. To identify senolytics, we treated the senescent population with the compounds of interest and found that ABT-737, navitoclax, chloroquine, ATMi, ATRi, BV-6, PX-866 and the natural compounds fisetin and artesunate exhibit senolytic activity, inducing death in senescent cells more efficiently than in proliferating cells. Curcumin showed the opposite effect. No specific effect on CSEN cells was observed by inhibition of Chk1/Chk2, p21, NF-kB, Rad51 and PARP. We conclude that these factors neither play a critical role in maintaining TMZ-induced CSEN nor can their inhibitors be considered as senolytics. Since IR and CCNU did not exhibit senolytic activity, radio- and chemotherapy with alkylating drugs is not designed to eliminate TMZ-induced senescent cancer cells.
    Keywords:  apoptosis; artesunate; cell death; cellular senescence; chloroquine; curcumin; fisetin; glioma; senolytics; temozolomide
    DOI:  https://doi.org/10.3390/cells11162588
  7. Neurooncol Adv. 2022 Jan-Dec;4(1):4(1): vdac017
    Superinduction of immunosuppressive glioblastoma extracellular vesicles by IFN-γ through PD-L1 and IDO1.
    Mi-Yeon Jung, Abudumijiti Aibaidula, Desmond A Brown, Benjamin T Himes, Luz M Cumba Garcia, Ian F Parney.
      Background: Glioblastoma (GBM), the most common primary brain tumor, has a median survival of 15-16 months. Immunotherapy is promising but GBM-mediated immunosuppression remains a barrier. GBMs express the interferon-gamma (IFN-γ)-responsive immunosuppressive molecules programmed cell death ligand 1 (PD-L1) and indoleamine 2,3-dioxygenase 1 (IDO1). Extracellular vesicles (EVs) have also been implicated in GBM-mediated immunosuppression, in part through PD-L1. We therefore sought to determine if GBM IFN-γ exposure increased GBM EV-mediated immunosuppression and mechanisms underlying this.Methods: Human GBM-derived cells were cultured in the presence/absence of IFN-γ. EVs were harvested. PD-L1, IDO1, and EV-associated protein expression was assessed. GBM EVs (+/-IFN-γ) were cultured with healthy donor monocytes. Immunosuppressive myeloid-derived suppressor cell (MDSC) and nonclassical monocyte (NCM) frequency was determined. Impact of GBM (+/-IFN-γ) EV-treated monocytes on CD3/CD28-mediated T cell proliferation was assessed. The impact of PD-L1 and IDO1 knockdown in GBM EVs in this system was evaluated.
    Results: IFN-γ exposure increased PD-L1 and IDO1 expression in GBM cells and EVs without altering EV size or frequency. IFN-γ-exposed GBM EVs induced more MDSC and NCM differentiation in monocytes and these monocytes caused more T cell inhibition than IFN-γ-naive GBM EVs. PD-L1 and/or IDO1 knockdown in GBM cells abrogated the immunosuppressive effects of IFN-γ-exposed GBM EVs on monocytes.
    Conclusions: IFN-γ exposure such as might occur during an antitumor immune response results in superinduction of GBM EVs' baseline immunosuppressive effects on monocytes. These effects are mediated by increased PD-L1 and IDO1 expression in GBM EVs. These data highlight mechanisms of GBM EV-mediated immunosuppression and identify therapeutic targets (PD-L1, IDO1) to reverse these effects.
    Keywords:  IDO1; PD-L1; extracellular vesicles (EVs); glioblastoma; interferon-gamma (IFN-γ)
    DOI:  https://doi.org/10.1093/noajnl/vdac017
  8. JAMA Oncol. 2022 Aug 25.
    World Health Organization 2021 Classification of Central Nervous System Tumors and Implications for Therapy for Adult-Type Gliomas: A Review.
    Tamar R Berger, Patrick Y Wen, Melanie Lang-Orsini, Ugonma N Chukwueke.
      Importance: Previous histologic classifications of brain tumors have been limited by discrepancies in diagnoses reported by neuropathologists and variability in outcomes and response to therapies. Such diagnostic discrepancies have impaired clinicians' ability to select the most appropriate therapies for patients and have allowed heterogeneous populations of patients to be enrolled in clinical trials, hindering the development of more effective therapies. In adult-type diffuse gliomas, histologic classification has a particularly important effect on clinical care.Observations: In 2021, the World Health Organization published the fifth edition of the Classification of Tumors of the Central Nervous System. This classification incorporates advances in understanding the molecular pathogenesis of brain tumors with histopathology in order to group tumors into more biologically and molecularly defined entities. As such, tumor classification is significantly improved through better characterized natural histories. These changes have particularly important implications for gliomas. For the first time, adult- and pediatric-type gliomas are classified separately on the basis of differences in molecular pathogenesis and prognosis. Furthermore, the previous broad category of adult-type diffuse gliomas has been consolidated into 3 types: astrocytoma, isocitrate dehydrogenase (IDH) mutant; oligodendroglioma, IDH mutant and 1p/19q codeleted; and glioblastoma, IDH wild type. These major changes are driven by IDH mutation status and include the restriction of the diagnosis of glioblastoma to tumors that are IDH wild type; the reclassification of tumors previously diagnosed as IDH-mutated glioblastomas as astrocytomas IDH mutated, grade 4; and the requirement for the presence of IDH mutations to classify tumors as astrocytomas or oligodendrogliomas.
    Conclusions and Relevance: The 2021 World Health Organization central nervous system tumor classification is a major advance toward improving the diagnosis of brain tumors. It will provide clinicians with more accurate guidance on prognosis and optimal therapy for patients and ensure that more homogenous patient populations are enrolled in clinical trials, potentially facilitating the development of more effective therapies.
    DOI:  https://doi.org/10.1001/jamaoncol.2022.2844
  9. Int J Mol Sci. 2022 Aug 17. pii: 9255. [Epub ahead of print]23(16):
    Targeting the Sphingolipid Rheostat in Gliomas.
    Faris Zaibaq, Tyrone Dowdy, Mioara Larion.
      Gliomas are highly aggressive cancer types that are in urgent need of novel drugs and targeted therapies. Treatment protocols have not improved in over a decade, and glioma patient survival remains among the worst of all cancer types. As a result, cancer metabolism research has served as an innovative approach to identifying novel glioma targets and improving our understanding of brain tumors. Recent research has uncovered a unique metabolic vulnerability in the sphingolipid pathways of gliomas that possess the IDH1 mutation. Sphingolipids are a family of lipid signaling molecules that play a variety of second messenger functions in cellular regulation. The two primary metabolites, sphingosine-1-phosphate (S1P) and ceramide, maintain a rheostat balance and play opposing roles in cell survival and proliferation. Altering the rheostat such that the pro-apoptotic signaling of the ceramides outweighs the pro-survival S1P signaling in glioma cells diminishes the hallmarks of cancer and enhances tumor cell death. Throughout this review, we discuss the sphingolipid pathway and identify the enzymes that can be most effectively targeted to alter the sphingolipid rheostat and enhance apoptosis in gliomas. We discuss each pathway's steps based on their site of occurrence in the organelles and postulate novel targets that can effectively exploit this vulnerability.
    Keywords:  brain tumors; ceramide; gliomas; isocitrate dehydrogenase 1 mutation; rheostat; sphingolipids; sphingosine-1-phosphate
    DOI:  https://doi.org/10.3390/ijms23169255
  10. Biomedicines. 2022 Aug 11. pii: 1943. [Epub ahead of print]10(8):
    Lipid Metabolism in Glioblastoma: From De Novo Synthesis to Storage.
    Yongjun Kou, Feng Geng, Deliang Guo.
      Glioblastoma (GBM) is the most lethal primary brain tumor. With limited therapeutic options, novel therapies are desperately needed. Recent studies have shown that GBM acquires large amounts of lipids for rapid growth through activation of sterol regulatory element-binding protein 1 (SREBP-1), a master transcription factor that regulates fatty acid and cholesterol synthesis, and cholesterol uptake. Interestingly, GBM cells divert substantial quantities of lipids into lipid droplets (LDs), a specific storage organelle for neutral lipids, to prevent lipotoxicity by increasing the expression of diacylglycerol acyltransferase 1 (DGAT1) and sterol-O-acyltransferase 1 (SOAT1), which convert excess fatty acids and cholesterol to triacylglycerol and cholesteryl esters, respectively. In this review, we will summarize recent progress on our understanding of lipid metabolism regulation in GBM to promote tumor growth and discuss novel strategies to specifically induce lipotoxicity to tumor cells through disrupting lipid storage, a promising new avenue for treating GBM.
    Keywords:  DGAT1; SOAT1; SREBP-1; cholesterol; fatty acids; glioblastoma; lipid droplets; lipotoxicity
    DOI:  https://doi.org/10.3390/biomedicines10081943
  11. Neurooncol Adv. 2022 Jan-Dec;4(1):4(1): vdac117
    An affinity for brainstem microglia in pediatric high-grade gliomas of brainstem origin.
    Liat Peretz Zats, Labiba Ahmad, Natania Casden, Meelim J Lee, Vitali Belzer, Orit Adato, Shaked Bar Cohen, Seung-Hyun B Ko, Mariella G Filbin, Ron Unger, Douglas A Lauffenburger, Rosalind A Segal, Oded Behar.
      Background: High-grade gliomas (HGG) in children have a devastating prognosis and occur in a remarkable spatiotemporal pattern. Diffuse midline gliomas (DMG), including diffuse intrinsic pontine gliomas (DIPG), typically occur in mid-childhood, while cortical HGGs are more frequent in older children and adults. The mechanisms behind this pattern are not clear.Methods: We used mouse organotypic slice cultures and glial cell cultures to test the impact of the microenvironment on human DIPG cells. Comparing the expression between brainstem and cortical microglia identified differentially expressed secreted proteins. The impact of some of these proteins on DIPGs was tested.
    Results: DIPGs, pediatric HGGs of brainstem origin, survive and divide more in organotypic slice cultures originating in the brainstem as compared to the cortex. Moreover, brainstem microglia are better able to support tumors of brainstem origin. A comparison between the two microglial populations revealed differentially expressed genes. One such gene, interleukin-33 (IL33), is highly expressed in the pons of young mice and its DIPG receptor is upregulated in this context. Consistent with this observation, the expression levels of IL33 and its receptor, IL1RL1, are higher in DIPG biopsies compared to low-grade cortical gliomas. Furthermore, IL33 can enhance proliferation and clonability of HGGs of brainstem origin, while blocking IL33 in brainstem organotypic slice cultures reduced the proliferation of these tumor cells.
    Conclusions: Crosstalk between DIPGs and the brainstem microenvironment, in particular microglia, through IL33 and other secreted factors, modulates spatiotemporal patterning of this HGG and could prove to be an important future therapeutic target.
    Keywords:  DIPG; interleukin-33; microglia; pediatric high-grade gliomas
    DOI:  https://doi.org/10.1093/noajnl/vdac117
  12. iScience. 2022 Aug 19. 25(8): 104823
    Targeting HOTAIRM1 ameliorates glioblastoma by disrupting mitochondrial oxidative phosphorylation and serine metabolism.
    Wei Han, Shanshan Wang, Yingjiao Qi, Fan Wu, Ningyu Tian, Boqin Qiang, Xiaozhong Peng.
      Serine hydroxymethyltransferase 2 (SHMT2), which catalyzes the conversion of serine to glycine and one-carbon transfer reactions in mitochondria, is significantly upregulated in glioblastoma (GBM). However, the mechanism by which the stability of SHMT2 gene expression is maintained to drive GBM tumorigenesis has not been clarified. Herein, through microarray screening, we identified that HOXA Transcript Antisense RNA, Myeloid-Specific 1 (HOTAIRM1) modulates the SHMT2 level in various GBM cell lines. Serine catabolism and mitochondrial oxidative phosphorylation activities were decreased by HOTAIRM1 inhibition. Mechanistically, according to our mass spectrometry and eCLIP-seq results, HOTAIRM1 can bind to PTBP1 and IGF2BP2. Furthermore, HOTAIRM1 maintains the stability of SHMT2 by promoting the recognition of an m6A site and the interaction of PTBP1/IGF2BP2 with SHMT2 mRNA. The stability of HOTAIRM1 can also be enhanced and results in positive feedback regulation to support the progression of GBM. Thus, targeting HOTAIRM1 could be a promising metabolic therapy for GBM.
    Keywords:  Cancer; Cell biology; Cellular physiology
    DOI:  https://doi.org/10.1016/j.isci.2022.104823
  13. Analyst. 2022 Aug 23.
    A novel quinoline-based fluorescent probe for real-time monitoring of Cys in glioma.
    Shang-Ming-Zhu Zeng, Qing Zhang, Qin Li, Liang-Chao Yuan, Muhammad Abbas, Zhen-Xiang He, Hai-Liang Zhu, Zhong-Chang Wang.
      Cysteine (Cys), a small-molecule biothiol, has recently been identified as a novel Glioblastoma (GBM) biomarker. The highly selective real-time monitoring and fluorescence imaging of Cys levels in vivo is of great significance for the early diagnosis and treatment of GBM. In this work, we reported a highly selective Cys fluorescent probe ZS-C1, based on quinoline according to the mechanism of the conjugate addition cyclization reaction. The Limit of Detection (LOD) of probe ZS-C1 was 1.97 μM, λex = 380 nm; λem = 531 nm. In vitro experiments showed that ZS-C1 could be distinguished from Hcy and GSH significantly, and the fluorescence quantum yield was reduced by 30 times. Further, biological imaging and 3D tumor sphere penetration assay showed that the ZS-C1 could monitor both exogenous and endogenous Cys in the living U87MG cells, and the fluorescence of probe ZS-C1 diffusely distributed inside the U87MG three-dimensional solid cell spheroid (up to 60 μM deep into the solid tumors). This work provided a potential tool for further investigations of Cys in biological samples and critical information for early diagnosis of glioma and guidance for clinical surgery.
    DOI:  https://doi.org/10.1039/d2an01115h
  14. Neurooncol Adv. 2022 Jan-Dec;4(1):4(1): vdac111
    Prognostic risk stratification of gliomas using deep learning in digital pathology images.
    Pranathi Chunduru, Joanna J Phillips, Annette M Molinaro.
      Background: Evaluation of tumor-tissue images stained with hematoxylin and eosin (H&E) is pivotal in diagnosis, yet only a fraction of the rich phenotypic information is considered for clinical care. Here, we propose a survival deep learning (SDL) framework to extract this information to predict glioma survival.Methods: Digitized whole slide images were downloaded from The Cancer Genome Atlas (TCGA) for 766 diffuse glioma patients, including isocitrate dehydrogenase (IDH)-mutant/1p19q-codeleted oligodendroglioma, IDH-mutant/1p19q-intact astrocytoma, and IDH-wildtype astrocytoma/glioblastoma. Our SDL framework employs a residual convolutional neural network with a survival model to predict patient risk from H&E-stained whole-slide images. We used statistical sampling techniques and randomized the transformation of images to address challenges in learning from histology images. The SDL risk score was evaluated in traditional and recursive partitioning (RPA) survival models.
    Results: The SDL risk score demonstrated substantial univariate prognostic power (median concordance index of 0.79 [se: 0.01]). After adjusting for age and World Health Organization 2016 subtype, the SDL risk score was significantly associated with overall survival (OS; hazard ratio = 2.45; 95% CI: 2.01 to 3.00). Four distinct survival risk groups were characterized by RPA based on SDL risk score, IDH status, and age with markedly different median OS ranging from 1.03 years to 14.14 years.
    Conclusions: The present study highlights the independent prognostic power of the SDL risk score for objective and accurate prediction of glioma outcomes. Further, we show that the RPA delineation of patient-specific risk scores and clinical prognostic factors can successfully demarcate the OS of glioma patients.
    Keywords:  H&E images; digital pathology; glioma; risk stratification; survival deep learning
    DOI:  https://doi.org/10.1093/noajnl/vdac111
  15. STAR Protoc. 2022 Sep 16. 3(3): 101607
    Protocol to analyze antitumor immunity of orthotopic injection and spontaneous murine high-grade glioma models using flow cytometry and single-cell RNA sequencing.
    Jang Hyun Park, Chae Won Kim, Hyun-Jin Kim, Hyun Jung Kim, Jeong Ho Lee, Heung Kyu Lee.
      Despite the recognized importance of antitumor immunity, our understanding of brain tumor immunity is poor. Orthotopic injection models have been widely used for immunological analyses. However, these models have limitations in analysis of antitumor immunity because the approach involves drilling skulls and injecting tumor cells, which can induce adverse effects. We describe a protocol for the induction of spontaneous brain tumor model, isolation of single cells from brain tumor microenvironment, and analysis of the immune responses using scRNA-seq and flow cytometry. For complete details on the use and execution of this protocol, please refer to Park et al. (2021).
    Keywords:  Cancer; Cell isolation; Flow cytometry/Mass cytometry; Immunology; Model organisms; Molecular biology; RNAseq; Sequencing; Single cell
    DOI:  https://doi.org/10.1016/j.xpro.2022.101607
  16. Front Oncol. 2022 ;12 781741
    Current understanding of the human microbiome in glioma.
    Jianhao Liang, Ting Li, Jiajia Zhao, Cheng Wang, Haitao Sun.
      There is mounting evidence that the human microbiome is highly associated with a wide variety of central nervous system diseases. However, the link between the human microbiome and glioma is rarely noticed. The exact mechanism of microbiota to affect glioma remains unclear. Recent studies have demonstrated that the microbiome may affect the development, progress, and therapy of gliomas, including the direct impacts of the intratumoral microbiome and its metabolites, and the indirect effects of the gut microbiome and its metabolites. Glioma-related microbiome (gut microbiome and intratumoral microbiome) is associated with both tumor microenvironment and tumor immune microenvironment, which ultimately influence tumorigenesis, progression, and responses to treatment. In this review, we briefly summarize current knowledge regarding the role of the glioma-related microbiome, focusing on its gut microbiome fraction and a brief description of the intratumoral microbiome, and put forward the prospects in which microbiome can be applied in the future and some challenges still need to be solved.
    Keywords:  glioma; gut microbiome; immune microenvironment; intratumoral microbiome; metabolism
    DOI:  https://doi.org/10.3389/fonc.2022.781741
  17. Cell Metab. 2022 Aug 19. pii: S1550-4131(22)00345-X. [Epub ahead of print]
    Aerobic glycolysis promotes tumor immune evasion by hexokinase2-mediated phosphorylation of IκBα.
    Dong Guo, Yingying Tong, Xiaoming Jiang, Ying Meng, Hongfei Jiang, Linyong Du, Qingang Wu, Shan Li, Shudi Luo, Min Li, Liwei Xiao, Haiyan He, Xuxiao He, Qiujing Yu, Jing Fang, Zhimin Lu.
      High expression of PD-L1 in tumor cells contributes to tumor immune evasion. However, whether PD-L1 expression in tumor cells is regulated by the availability of nutrients is unknown. Here, we show that in human glioblastoma cells, high glucose promotes hexokinase (HK) 2 dissociation from mitochondria and its subsequent binding and phosphorylation of IκBα at T291. This leads to increased interaction between IκBα and μ-calpain protease and subsequent μ-calpain-mediated IκBα degradation and NF-κB activation-dependent transcriptional upregulation of PD-L1 expression. Expression of IκBα T291A in glioblastoma cells blocked high glucose-induced PD-L1 expression and promoted CD8+ T cell activation and infiltration into the tumor tissue, reducing brain tumor growth. Combined treatment with an HK inhibitor and an anti-PD-1 antibody eliminates tumor immune evasion and remarkably enhances the anti-tumor effect of immune checkpoint blockade. These findings elucidate a novel mechanism underlying the upregulation of PD-L1 expression mediated by aerobic glycolysis and underscore the roles of HK2 as a glucose sensor and a protein kinase in regulation of tumor immune evasion.
    Keywords:  HK2; IκBα; NF-κB; PD-L1; glycolysis; immune evasion; phosphorylation; protein kinase
    DOI:  https://doi.org/10.1016/j.cmet.2022.08.002
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