bims-malgli Biomed News
on Biology of malignant gliomas
Issue of 2022–12–25
eleven papers selected by
Oltea Sampetrean, Keio University
  1. Rhythmic Ca2+ Communication Promotes Glioma Cell Proliferation.
  2. Treating glioblastoma often makes a MES.
  3. ALDH1-Mediated Autophagy Sensitizes Glioblastoma Cells to Ferroptosis.
  4. A single-cell atlas of glioblastoma evolution under therapy reveals cell-intrinsic and cell-extrinsic therapeutic targets.
  5. Tumor BOLD connectivity profile correlates with glioma patients' survival.
  6. A prognostic risk model for glioma patients by systematic evaluation of genomic variations.
  7. BRD8 maintains glioblastoma by epigenetic reprogramming of the p53 network.
  8. Methionine regulates self-renewal, pluripotency, and cell death of GIC through cholesterol-rRNA axis.
  9. Autologous Tumor Lysate-Loaded Dendritic Cell Vaccination (DCVax-L) in glioblastoma: breakthrough or fata morgana?
  10. Australian genome-wide association study confirms higher female risk for adult glioma associated with variants in the region of CCDC26.
  11. ALT in Pediatric High-Grade Gliomas Can Occur without ATRX Mutation and is Enriched in Patients with Pathogenic Germline MMR Variants.
  1. Cancer Discov. 2022 Dec 22. OF1
    Rhythmic Ca2+ Communication Promotes Glioma Cell Proliferation.
      A plastic glioblastoma cell population exhibits rhythmic Ca2+ oscillations that drive brain tumor growth.
    DOI:  https://doi.org/10.1158/2159-8290.CD-RW2022-225
  2. Nat Cancer. 2022 Dec;3(12): 1446-1448
    Treating glioblastoma often makes a MES.
    Lucy F Stead.
      
    DOI:  https://doi.org/10.1038/s43018-022-00471-1
  3. Cells. 2022 Dec 12. pii: 4015. [Epub ahead of print]11(24):
    ALDH1-Mediated Autophagy Sensitizes Glioblastoma Cells to Ferroptosis.
    Yang Wu, Helena Kram, Jens Gempt, Friederike Liesche-Starnecker, Wei Wu, Jürgen Schlegel.
      The fatal clinical course of human glioblastoma (GBM) despite aggressive adjuvant therapies is due to high rates of recurrent tumor growth driven by tumor cells with stem-cell characteristics (glioma stem cells, GSCs). The aldehyde dehydrogenase 1 (ALDH1) family of enzymes has been shown to be a biomarker for GSCs, and ALDH1 seems to be involved in the biological processes causing therapy resistance. Ferroptosis is a recently discovered cell death mechanism, that depends on iron overload and lipid peroxidation, and it could, therefore, be a potential therapeutic target in various cancer types. Since both ALDH1 and ferroptosis interact with lipid peroxidation (LPO), we aimed to investigate a possible connection between ALDH1 and ferroptosis. Here, we show that RSL3-induced LPO and ferroptotic cell death revealed RSL3-sensitive and -resistant malignant glioma cell lines. Most interestingly, RSL3 sensitivity correlates with ALDH1a3 expression; only high ALDH1a3-expressing cells seem to be sensitive to ferroptosis induction. In accordance, inhibition of ALDH1a3 enzymatic activity by chemical inhibition or genetic knockout protects tumor cells from RSL3-induced ferroptotic cell death. Both RSL-3-dependent binding of ALDH1a3 to LC3B and autophagic downregulation of ferritin could be completely blocked by ALDH inhibition. Therefore, ALDH1a3 seems to be involved in ferroptosis through the essential release of iron by ferritinophagy. Our results also indicate that ferroptosis induction might be a particularly interesting clinical approach for targeting the highly aggressive cell population of GSC.
    Keywords:  autophagy; cancer stem cells; ferroptosis; glioblastoma; therapy
    DOI:  https://doi.org/10.3390/cells11244015
  4. Nat Cancer. 2022 Dec;3(12): 1534-1552
    A single-cell atlas of glioblastoma evolution under therapy reveals cell-intrinsic and cell-extrinsic therapeutic targets.
    Lin Wang, Jangham Jung, Husam Babikir, Karin Shamardani, Saket Jain, Xi Feng, Nalin Gupta, Susanna Rosi, Susan Chang, David Raleigh, David Solomon, Joanna J Phillips, Aaron A Diaz.
      Recent longitudinal studies of glioblastoma (GBM) have demonstrated a lack of apparent selection pressure for specific DNA mutations in recurrent disease. Single-cell lineage tracing has shown that GBM cells possess a high degree of plasticity. Together this suggests that phenotype switching, as opposed to genetic evolution, may be the escape mechanism that explains the failure of precision therapies to date. We profiled 86 primary-recurrent patient-matched paired GBM specimens with single-nucleus RNA, single-cell open-chromatin, DNA and spatial transcriptomic/proteomic assays. We found that recurrent GBMs are characterized by a shift to a mesenchymal phenotype. We show that the mesenchymal state is mediated by activator protein 1. Increased T-cell abundance at recurrence was prognostic and correlated with hypermutation status. We identified tumor-supportive networks of paracrine and autocrine signals between GBM cells, nonmalignant neuroglia and immune cells. We present cell-intrinsic and cell-extrinsic targets and a single-cell multiomics atlas of GBM under therapy.
    DOI:  https://doi.org/10.1038/s43018-022-00475-x
  5. Neurooncol Adv. 2022 Jan-Dec;4(1):4(1): vdac153
    Tumor BOLD connectivity profile correlates with glioma patients' survival.
    Giulia Sprugnoli, Laura Rigolo, Meghan Faria, Parikshit Juvekar, Yanmei Tie, Simone Rossi, Nicola Sverzellati, Alexandra J Golby, Emiliano Santarnecchi.
       Background: Presence of residual neurovascular activity within glioma lesions have been recently demonstrated via functional MRI (fMRI) along with active electrical synapses between glioma cells and healthy neurons that influence survival. In this study, we aimed to investigate whether gliomas demonstrate synchronized neurovascular activity with the rest of the brain, by measuring Blood Oxygen Level Dependent (BOLD) signal synchronization, that is, functional connectivity (FC), while also testing whether the strength of such connectivity might predict patients' overall survival (OS).
    Methods: Resting-state fMRI scans of patients who underwent pre-surgical brain mapping were analyzed (total sample, n = 54; newly diagnosed patients, n = 18; recurrent glioma group, n = 36). A seed-to-voxel analysis was conducted to estimate the FC signal profile of the tumor mass. A regression model was then built to investigate the potential correlation between tumor FC and individual OS. Finally, an unsupervised, cross-validated clustering analysis was performed including tumor FC and clinical OS predictors (e.g., Karnofsky Performance Status - KPS - score, tumor volume, and genetic profile) to verify the performance of tumor FC in predicting OS with respect to validated radiological, demographic, genetic and clinical prognostic factors.
    Results: In both newly diagnosed and recurrent glioma patients a significant pattern of BOLD synchronization between the solid tumor and distant brain regions was found. Crucially, glioma-brain FC positively correlated with variance in individual survival in both newly diagnosed glioma group (r = 0.90-0.96; P < .001; R 2 = 81-92%) and in the recurrent glioma group (r = 0.72; P < .001; R 2 = 52%), outperforming standard clinical, radiological and genetic predictors.
    Conclusions: Results suggest glioma's synchronization with distant brain regions should be further explored as a possible diagnostic and prognostic biomarker.
    Keywords:  brain tumor; fMRI; functional connectivity; overall survival; predictor
    DOI:  https://doi.org/10.1093/noajnl/vdac153
  6. iScience. 2022 Dec 22. 25(12): 105681
    A prognostic risk model for glioma patients by systematic evaluation of genomic variations.
    Baifeng Zhang, Weiqing Wan, Zibo Li, Zhixian Gao, Nan Ji, Jian Xie, Junmei Wang, Bin Wang, Dora Lai-Wan Kwong, Xinyuan Guan, Shengjie Gao, Yuanli Zhao, Youyong Lu, Liwei Zhang, Karin D Rodland, Shirley X Tsang.
      The overall survival rate of gliomas has not significantly improved despite new effective treatments, mainly due to tumor heterogeneity and drug delivery. Here, we perform an integrated clinic-genomic analysis of 1, 477 glioma patients from a Chinese cohort and a TCGA cohort and propose a potential prognostic model for gliomas. We identify that SBS11 and SBS23 mutational signatures are associated with glioma recurrence and indicate worse prognosis only in low-grade type of gliomas and IDH-Mut subtype. We also identify 42 genomic features associated with distinct clinical outcome and successfully used ten of these to develop a prognostic risk model of gliomas. The high-risk glioma patients with shortened survival were characterized by high level of frequent copy number alterations including PTEN, CDKN2A/B deletion, EGFR amplification, less IDH1 or CIC gene mutations, high infiltration levels of immunosuppressive cells and activation of G2M checkpoint and Oxidative phosphorylation oncogenic pathway.
    Keywords:  Cancer; Genetics; Genomics
    DOI:  https://doi.org/10.1016/j.isci.2022.105681
  7. Nature. 2022 Dec 21.
    BRD8 maintains glioblastoma by epigenetic reprogramming of the p53 network.
    Xueqin Sun, Olaf Klingbeil, Bin Lu, Caizhi Wu, Carlos Ballon, Meng Ouyang, Xiaoli S Wu, Ying Jin, Yon Hwangbo, Yu-Han Huang, Tim D D Somerville, Kenneth Chang, Jung Park, Taemoon Chung, Scott K Lyons, Junwei Shi, Hannes Vogel, Michael Schulder, Christopher R Vakoc, Alea A Mills.
      Inhibition of the tumour suppressive function of p53 (encoded by TP53) is paramount for cancer development in humans. However, p53 remains unmutated in the majority of cases of glioblastoma (GBM)-the most common and deadly adult brain malignancy1,2. Thus, how p53-mediated tumour suppression is countered in TP53 wild-type (TP53WT) GBM is unknown. Here we describe a GBM-specific epigenetic mechanism in which the chromatin regulator bromodomain-containing protein 8 (BRD8) maintains H2AZ occupancy at p53 target loci through the EP400 histone acetyltransferase complex. This mechanism causes a repressive chromatin state that prevents transactivation by p53 and sustains proliferation. Notably, targeting the bromodomain of BRD8 displaces H2AZ, enhances chromatin accessibility and engages p53 transactivation. This in turn enforces cell cycle arrest and tumour suppression in TP53WT GBM. In line with these findings, BRD8 is highly expressed with H2AZ in proliferating single cells of patient-derived GBM, and is inversely correlated with CDKN1A, a canonical p53 target that encodes p21 (refs. 3,4). This work identifies BRD8 as a selective epigenetic vulnerability for a malignancy for which treatment has not improved for decades. Moreover, targeting the bromodomain of BRD8 may be a promising therapeutic strategy for patients with TP53WT GBM.
    DOI:  https://doi.org/10.1038/s41586-022-05551-x
  8. BMC Cancer. 2022 Dec 23. 22(1): 1351
    Methionine regulates self-renewal, pluripotency, and cell death of GIC through cholesterol-rRNA axis.
    Kiyotaka Yokogami, Taisei Kikuchi, Takashi Watanabe, Yasutaka Nakatake, Shinji Yamashita, Asako Mizuguchi, Hideo Takeshima.
       BACKGROUND: Glioma-initiating cells (GICs) are the source of glioma cells that can self-renew, have pluripotency, and are treatment-resistant, so are the starting point for relapse and eventual death despite multimodality therapy. L-[methyl-11C] methionine PET has observed high accumulation at the time of recurrence, it is important to understand the mechanism of tumor cell activation caused by the reorganization of methionine metabolism.  METHODS: We cultured cells in methionine-deprived culture medium for comprehensive analysis. Based on the obtained results, the possible target molecules were chemically inhibited and the respective markers were analyzed.
    RESULTS: Methionine depletion markedly decreased proliferation and increased cell death of GICs. Decreased S-adenosyl-methionine, which is synthesized intracellularly by catalyzed by methionine adenosyltransferase using methionine, triggered the following: (i) global DNA demethylation, (ii) hyper-methylation of signaling pathways regulating pluripotency of stem cells, (iii) decreased expression of the core-genes and pluripotent markers of stem cells including FOXM1, SOX2, SOX4, PROM1, and OLIG2, (iv) decreased cholesterol synthesis and increased excretion mainly through decreased SREBF2, and (v) down-regulation of the large subunit of ribosomal protein configured 28S and ACA43, small nucleolar RNA guiding the pseudouridylation of 28S rRNA, which is essential for translation. In addition, inhibition of cholesterol synthesis with statin resulted in a phenotype similar to that of methionine depletion and decreases in stem cell markers and small nucleolar RNA ACA43. Moreover, suppression of FOXM1 decreased stem cell markers such as SOX4 and PROM1. The gene expression profile for cholesterol production was obtained from the Ivy Glioblastoma Atlas Project database and compared between tumor cells with relatively low methionine levels in areas of pseudopalisading arrangement around necrosis and tumor cells in the infiltrating region, showing that cells in the infiltrating region have higher capacity to produce cholesterol.
    CONCLUSIONS: Methionine metabolism is closely related with self-renewal, pluripotency, and cell death in GICs through modification of cholesterol biosynthesis, especially in the SREBF2-FOXM1 and ACA43 axis with modification of rRNA.
    Keywords:  ACA43; Cholesterol biosynthesis; GIC; Methionine; rRNA
    DOI:  https://doi.org/10.1186/s12885-022-10280-5
  9. Neuro Oncol. 2022 Dec 23. pii: noac281. [Epub ahead of print]
    Autologous Tumor Lysate-Loaded Dendritic Cell Vaccination (DCVax-L) in glioblastoma: breakthrough or fata morgana?
    Matthias Preusser, Martin J van den Bent.
      
    Keywords:  Confounding factors; DCVax-L; External controls; Glioblastoma
    DOI:  https://doi.org/10.1093/neuonc/noac281
  10. Neuro Oncol. 2022 Dec 20. pii: noac279. [Epub ahead of print]
    Australian genome-wide association study confirms higher female risk for adult glioma associated with variants in the region of CCDC26.
    Karen Alpen, Claire M Vajdic, Robert J MacInnis, Roger L Milne, Eng-Siew Koh, Elizabeth Hovey, Rosemary Harrup, Fiona Bruinsma, Tuong L Nguyen, Shuai Li, David Joseph, Geza Benke, Pierre-Antoine Dugué, Melissa C Southey, Graham G Giles, Mark Rosenthal, Katharine J Drummond, Anna K Nowak, John L Hopper, Miroslaw Kapuscinski, Enes Makalic.
       BACKGROUND: Glioma accounts for approximately 80% of malignant adult brain cancer and its most common subtype, glioblastoma, has one of the lowest 5-year cancer survivals. Fifty risk-associated variants within 34 glioma genetic risk regions have been found by genome-wide association studies (GWAS) with a sex difference reported for 8q24.21 region. We conducted an Australian GWAS by glioma subtype and sex.
    METHODS: We analysed genome-wide data from the Australian Genomics and Clinical Outcomes of Glioma (AGOG) consortium for 7,573,692 single nucleotide polymorphisms (SNPs) for 560 glioma cases and 2,237 controls of European ancestry. Cases were classified as glioblastoma, non-glioblastoma, astrocytoma or oligodendroglioma Logistic regression analysis was used to assess the associations of SNPs with glioma risk by subtype and by sex.
    RESULTS: We replicated the previously reported glioma risk associations in the regions of 2q33.3 C2orf80, 2q37.3 D2HGDH, 5p15.33 TERT, 7p11.2 EGFR, 8q24.21 CCDC26, 9p21.3 CDKN2BAS, 11q21 MAML2, 11q23.3 PHLDB1, 15q24.2 ETFA, 16p13.3 RHBDF1, 16p13.3 LMF1, 17p13.1 TP53, 20q13.33 RTEL and 20q13.33 GMEB2 (P<0.05). We also replicated the previously reported sex difference at 8q24.21 CCDC26 (P=0.0024) with the association being nominally significant for both sexes (P<0.05).
    CONCLUSIONS: Our study supports a stronger female risk association for the region 8q24.21 CCDC26 and highlights the importance of analysing glioma GWAS by sex. A better understanding of sex differences could provide biological insight into the cause of glioma with implications for prevention, risk prediction and treatment.
    Keywords:   CCDC26 ; GWAS; glioblastoma; glioma; sex differences
    DOI:  https://doi.org/10.1093/neuonc/noac279
  11. Neuro Oncol. 2022 Dec 20. pii: noac278. [Epub ahead of print]
    ALT in Pediatric High-Grade Gliomas Can Occur without ATRX Mutation and is Enriched in Patients with Pathogenic Germline MMR Variants.
    Jennifer L Stundon, Heba Ijaz, Krutika S Gaonkar, Rebecca S Kaufman, Run Jin, Anastasios Karras, Zalman Vaksman, Jung Kim, Ryan J Corbett, Matthew R Lueder, Daniel P Miller, Yiran Guo, Mariarita Santi, Marilyn Li, Gonzalo Lopez, Phillip B Storm, Adam C Resnick, Angela J Waanders, Suzanne P MacFarland, Douglas R Stewart, Sharon J Diskin, Jo Lynne Rokita, Kristina A Cole.
       BACKGROUND: To achieve replicative immortality, most cancers develop a telomere maintenance mechanism, such as reactivation of telomerase or alternative lengthening of telomeres (ALT). There are limited data on the prevalence and clinical significance of ALT in pediatric brain tumors, and ALT-directed therapy is not available.
    METHODS: We performed C-circle analysis (CCA) on 579 pediatric brain tumors that had corresponding tumor/normal whole genome sequencing through the Open Pediatric Brain Tumor Atlas (OpenPBTA). We detected ALT in 6.9% (n=40/579) of these tumors and completed additional validation by ultrabright telomeric foci in situ on a subset of these tumors. We used CCA to validate TelomereHunter for computational prediction of ALT status and focus subsequent analyses on pediatric high-grade glioma (pHGG) Finally, we examined whether ALT is associated with recurrent somatic or germline alterations.
    RESULTS: ALT is common in pHGG (n=24/63, 38.1%), but occurs infrequently in other pediatric brain tumors (<3%). Somatic ATRX mutations occur in 50% of ALT+ pHGG and in 30% of ALT- pHGG. Rare pathogenic germline variants in mismatch repair (MMR) genes are significantly associated with an increased occurrence of ALT.
    CONCLUSIONS: We demonstrate that ATRX is mutated in only a subset of ALT+ pHGG, suggesting other mechanisms of ATRX loss of function or alterations in other genes may be associated with the development of ALT in these patients. We show that germline variants in MMR are associated with development of ALT in patients with pHGG.
    Keywords:  ATRX; Alternative lengthening of telomeres; Telomere; mismatch repair; pHGG; pediatric brain tumors
    DOI:  https://doi.org/10.1093/neuonc/noac278
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