bims-malgli Biomed News
on Biology of malignant gliomas
Issue of 2024–01–21
eleven papers selected by
Oltea Sampetrean, Keio University
  1. Understanding and therapeutically exploiting cGAS/STING signaling in glioblastoma.
  2. Regnase-2 inhibits glioblastoma cell proliferation.
  3. Glioblastoma evolution and heterogeneity from a 3D whole-tumor perspective.
  4. Triggering receptor expressed on myeloid cells 2 (TREM2) regulates phagocytosis in glioblastoma.
  5. Homeostatic iron regulatory protein drives glioblastoma growth via tumor cell-intrinsic and sex-specific responses.
  6. The genomic alterations in glioblastoma influence the levels of CSF metabolites.
  7. Exploring the multifaceted role of NRF2 in brain physiology and cancer: A comprehensive review.
  8. miRNA-194-3p represses NF-κB in gliomas to attenuate iPSC genes and proneural to mesenchymal transition.
  9. A holistic view of the malignant organism we call glioblastoma.
  10. Treatment-associated imaging changes in newly diagnosed MGMT promoter-methylated glioblastoma undergoing chemoradiation with or without cilengitide.
  11. Enrichment of a neutrophil-like monocyte transcriptional state in glioblastoma myeloid suppressor cells.
  1. J Clin Invest. 2024 Jan 16. pii: e163452. [Epub ahead of print]134(2):
    Understanding and therapeutically exploiting cGAS/STING signaling in glioblastoma.
    Justin T Low, Michael C Brown, Zachary J Reitman, Joshua D Bernstock, James M Markert, Gregory K Friedman, Matthew S Waitkus, Michelle L Bowie, David M Ashley.
      Since the discovery that cGAS/STING recognizes endogenous DNA released from dying cancer cells and induces type I interferon and antitumor T cell responses, efforts to understand and therapeutically target the STING pathway in cancer have ensued. Relative to other cancer types, the glioma immune microenvironment harbors few infiltrating T cells, but abundant tumor-associated myeloid cells, possibly explaining disappointing responses to immune checkpoint blockade therapies in cohorts of patients with glioblastoma. Notably, unlike most extracranial tumors, STING expression is absent in the malignant compartment of gliomas, likely due to methylation of the STING promoter. Nonetheless, several preclinical studies suggest that inducing cGAS/STING signaling in the glioma immune microenvironment could be therapeutically beneficial, and cGAS/STING signaling has been shown to mediate inflammatory and antitumor effects of other modalities either in use or being developed for glioblastoma therapy, including radiation, tumor-treating fields, and oncolytic virotherapy. In this Review, we discuss cGAS/STING signaling in gliomas, its implications for glioma immunobiology, compartment-specific roles for STING signaling in influencing immune surveillance, and efforts to target STING signaling - either directly or indirectly - for antiglioma therapy.
    DOI:  https://doi.org/10.1172/JCI163452
  2. Sci Rep. 2024 01 18. 14(1): 1574
    Regnase-2 inhibits glioblastoma cell proliferation.
    Weronika Sowinska, Mateusz Wawro, Jakub Kochan, Aleksandra Solecka, Jarosław Polak, Borys Kwinta, Aneta Kasza.
      Regnase-2 (Reg-2/MCPIP2/ZC3H12B) is uniquely expressed at a high level in the healthy brain and down-regulated in samples from patients with glioma, reaching the lowest level in high-grade glioblastoma multiforme (GBM). This RNase is involved in the regulation of neuroinflammation through the degradation of IL-6 and IL-1 mRNAs, key pro-inflammatory cytokines for GBM pathology. Reg-2 is a strong inhibitor of the proliferation of human glioblastoma cell lines and blocks their potential to form colonies. Here, we describe that overexpression of Reg-2 stalls glioblastoma cells in the G1 phase of the cell cycle and reduces the level of transcripts implicated in cell cycle progression. These newly identified targets include CCND1, CCNE1, CCNE2, CCNA2, CCNB1, and CCNB2, encoding the cyclins as well as AURKA and PLK1, encoding two important mitosis regulators. By RNA immunoprecipitation we confirmed the direct interaction of Reg-2 with the investigated transcripts. We also tested mRNA regions involved in their interaction with Reg-2 on the example of CCNE2. Reg-2 interacts with the 3'UTR of CCNE2 in a dose-dependent manner. In conclusion, our results indicate that Reg-2 controls key elements in GBM biology by restricting neuroinflammation and inhibiting cancer cell proliferation.
    DOI:  https://doi.org/10.1038/s41598-024-51809-x
  3. Cell. 2024 Jan 18. pii: S0092-8674(23)01345-4. [Epub ahead of print]187(2): 446-463.e16
    Glioblastoma evolution and heterogeneity from a 3D whole-tumor perspective.
    Radhika Mathur, Qixuan Wang, Patrick G Schupp, Ana Nikolic, Stephanie Hilz, Chibo Hong, Nadia R Grishanina, Darwin Kwok, Nicholas O Stevers, Qiushi Jin, Mark W Youngblood, Lena Ann Stasiak, Ye Hou, Juan Wang, Takafumi N Yamaguchi, Marisa Lafontaine, Anny Shai, Ivan V Smirnov, David A Solomon, Susan M Chang, Shawn L Hervey-Jumper, Mitchel S Berger, Janine M Lupo, Hideho Okada, Joanna J Phillips, Paul C Boutros, Marco Gallo, Michael C Oldham, Feng Yue, Joseph F Costello.
      Treatment failure for the lethal brain tumor glioblastoma (GBM) is attributed to intratumoral heterogeneity and tumor evolution. We utilized 3D neuronavigation during surgical resection to acquire samples representing the whole tumor mapped by 3D spatial coordinates. Integrative tissue and single-cell analysis revealed sources of genomic, epigenomic, and microenvironmental intratumoral heterogeneity and their spatial patterning. By distinguishing tumor-wide molecular features from those with regional specificity, we inferred GBM evolutionary trajectories from neurodevelopmental lineage origins and initiating events such as chromothripsis to emergence of genetic subclones and spatially restricted activation of differential tumor and microenvironmental programs in the core, periphery, and contrast-enhancing regions. Our work depicts GBM evolution and heterogeneity from a 3D whole-tumor perspective, highlights potential therapeutic targets that might circumvent heterogeneity-related failures, and establishes an interactive platform enabling 360° visualization and analysis of 3D spatial patterns for user-selected genes, programs, and other features across whole GBM tumors.
    Keywords:  brain tumors; chromatin accessibility; chromatin interactions; epigenomics; genomics; glioblastoma; intratumoral heterogeneity; microenvironment; spatial analysis; tumor evolution
    DOI:  https://doi.org/10.1016/j.cell.2023.12.013
  4. Neuro Oncol. 2024 Jan 18. pii: noad257. [Epub ahead of print]
    Triggering receptor expressed on myeloid cells 2 (TREM2) regulates phagocytosis in glioblastoma.
    Mekenzie M Peshoff, Pravesh Gupta, Shivangi Oberai, Rakesh Trivedi, Hiroshi Katayama, Prashanth Chakrapani, Minghao Dang, Simona Migliozzi, Joy Gumin, Divya B Kadri, Jessica K Lin, Nancy K Milam, Mark E Maynard, Brian D Vaillant, Brittany Parker-Kerrigan, Frederick F Lang, Jason T Huse, Antonio Iavarone, Linghua Wang, Karen Clise-Dwyer, Krishna P Bhat.
       BACKGROUND: Glioblastomas (GBMs) are central nervous system tumors that resist standard of care interventions and even immune checkpoint blockade. Myeloid cells in the tumor microenvironment can contribute to GBM progression; therefore, emerging immunotherapeutic approaches include reprogramming these cells to achieve desirable anti-tumor activity. Triggering receptor expressed on myeloid cells 2 (TREM2) is a myeloid signaling regulator that has been implicated in a variety of cancers and neurological diseases with contrasting functions, but its role in GBM immunopathology and progression is still under investigation.
    METHODS: Our reverse translational investigations leveraged single-cell RNA sequencing and cytometry of human gliomas to characterize TREM2 expression across myeloid subpopulations. Using two distinct murine glioma models, we examined the role of Trem2 on tumor progression and immune modulation of myeloid cells. Furthermore, we designed a method of tracking phagocytosis of glioma cells in vivo and employed in vitro assays to mechanistically understand the influence of TREM2 signaling on tumor uptake.
    RESULTS: We discovered that TREM2 expression does not correlate with immunosuppressive pathways, but rather showed strong positive association with the canonical phagocytosis markers lysozyme (LYZ) and macrophage scavenger receptor (CD163) in gliomas. While Trem2 deficiency was found to be dispensable for gliomagenesis, Trem2+ myeloid cells display enhanced tumor uptake compared to Trem2- cells. Mechanistically, we demonstrate that TREM2 mediates phagocytosis via Syk signaling.
    CONCLUSIONS: These results indicate that TREM2 is not associated with immunosuppression in gliomas. Instead, TREM2 is an important regulator of phagocytosis that may be exploited as a potential therapeutic strategy for brain tumors.
    Keywords:  TREM2; glioblastoma; microglia; phagocytosis
    DOI:  https://doi.org/10.1093/neuonc/noad257
  5. Neurooncol Adv. 2024 Jan-Dec;6(1):6(1): vdad154
    Homeostatic iron regulatory protein drives glioblastoma growth via tumor cell-intrinsic and sex-specific responses.
    Katie M Troike, Sabrina Z Wang, Daniel J Silver, Juyeun Lee, Erin E Mulkearns-Hubert, Nicole Hajdari, Prabar K Ghosh, Kristen E Kay, Julia L Beilis, Sofia E Mitchell, Christopher W Bishop, Ellen S Hong, Mykyta Artomov, Christopher G Hubert, Prajwal Rajappa, James R Connor, Paul L Fox, Bjarne W Kristensen, Justin D Lathia.
       Background: Glioblastoma (GBM) displays alterations in iron that drive proliferation and tumor growth. Iron regulation is complex and involves many regulatory mechanisms, including the homeostatic iron regulator (HFE) gene, which encodes the homeostatic iron regulatory protein. While HFE is upregulated in GBM and correlates with poor survival outcomes, the function of HFE in GBM remains unclear.
    Methods: We interrogated the impact of cell-intrinsic Hfe expression on proliferation and survival of intracranially implanted animals through genetic gain- and loss-of-function approaches in syngeneic mouse glioma models, along with in vivo immune assessments. We also determined the expression of iron-associated genes and their relationship to survival in GBM using public data sets and used transcriptional profiling to identify differentially expressed pathways in control compared to Hfe-knockdown cells.
    Results: Overexpression of Hfe accelerated GBM proliferation and reduced animal survival, whereas suppression of Hfe induced apoptotic cell death and extended survival, which was more pronounced in females and associated with attenuation of natural killer cells and CD8+ T cell activity. Analysis of iron gene signatures in Hfe-knockdown cells revealed alterations in the expression of several iron-associated genes, suggesting global disruption of intracellular iron homeostasis. Further analysis of differentially expressed pathways revealed oxidative stress as the top pathway upregulated following Hfe loss. Hfe knockdown indeed resulted in enhanced 55Fe uptake and generation of reactive oxygen species.
    Conclusions: These findings reveal an essential function for HFE in GBM cell growth and survival, as well as a sex-specific interaction with the immune response.
    Keywords:  HFE; glioblastoma; iron; reactive oxygen species; sex difference
    DOI:  https://doi.org/10.1093/noajnl/vdad154
  6. Acta Neuropathol Commun. 2024 Jan 19. 12(1): 13
    The genomic alterations in glioblastoma influence the levels of CSF metabolites.
    Daniel H Wang, Yoko Fujita, Antonio Dono, Ana G Rodriguez Armendariz, Mauli Shah, Nagireddy Putluri, Pavel S Pichardo-Rojas, Chirag B Patel, Jay-Jiguang Zhu, Jason T Huse, Brittany C Parker Kerrigan, Frederick F Lang, Yoshua Esquenazi, Leomar Y Ballester.
      Cerebrospinal fluid (CSF) analysis is underutilized in patients with glioblastoma (GBM), partly due to a lack of studies demonstrating the clinical utility of CSF biomarkers. While some studies show the utility of CSF cell-free DNA analysis, studies analyzing CSF metabolites in patients with glioblastoma are limited. Diffuse gliomas have altered cellular metabolism. For example, mutations in isocitrate dehydrogenase enzymes (e.g., IDH1 and IDH2) are common in diffuse gliomas and lead to increased levels of D-2-hydroxyglutarate in CSF. However, there is a poor understanding of changes CSF metabolites in GBM patients. In this study, we performed targeted metabolomic analysis of CSF from n = 31 patients with GBM and n = 13 individuals with non-neoplastic conditions (controls), by mass spectrometry. Hierarchical clustering and sparse partial least square-discriminant analysis (sPLS-DA) revealed differences in CSF metabolites between GBM and control CSF, including metabolites associated with fatty acid oxidation and the gut microbiome (i.e., carnitine, 2-methylbutyrylcarnitine, shikimate, aminobutanal, uridine, N-acetylputrescine, and farnesyl diphosphate). In addition, we identified differences in CSF metabolites in GBM patients based on the presence/absence of TP53 or PTEN mutations, consistent with the idea that different mutations have different effects on tumor metabolism. In summary, our results increase the understanding of CSF metabolites in patients with diffuse gliomas and highlight several metabolites that could be informative biomarkers in patients with GBM.
    Keywords:  Biomarker; CSF; Carnitine; Cerebrospinal fluid; Choline; GABA; Glioblastoma; Lactate; Metabolomics; PTEN; Shikimate; TP53
    DOI:  https://doi.org/10.1186/s40478-024-01722-1
  7. Neurooncol Adv. 2024 Jan-Dec;6(1):6(1): vdad160
    Exploring the multifaceted role of NRF2 in brain physiology and cancer: A comprehensive review.
    Maya M Moubarak, Antonio C Pagano Zottola, Claire M Larrieu, Sylvain Cuvellier, Thomas Daubon, Océane C B Martin.
      Chronic oxidative stress plays a critical role in the development of brain malignancies due to the high rate of brain oxygen utilization and concomitant production of reactive oxygen species. The nuclear factor-erythroid-2-related factor 2 (NRF2), a master regulator of antioxidant signaling, is a key factor in regulating brain physiology and the development of age-related neurodegenerative diseases. Also, NRF2 is known to exert a protective antioxidant effect against the onset of oxidative stress-induced diseases, including cancer, along with its pro-oncogenic activities through regulating various signaling pathways and downstream target genes. In glioblastoma (GB), grade 4 glioma, tumor resistance, and recurrence are caused by the glioblastoma stem cell population constituting a small bulk of the tumor core. The persistence and self-renewal capacity of these cell populations is enhanced by NRF2 expression in GB tissues. This review outlines NRF2's dual involvement in cancer and highlights its regulatory role in human brain physiology and diseases, in addition to the development of primary brain tumors and therapeutic potential, with a focus on GB.
    Keywords:  Brain physiology; NRF2; glioblastoma stem cells; oxidative stress; therapeutic resistance
    DOI:  https://doi.org/10.1093/noajnl/vdad160
  8. iScience. 2024 Jan 19. 27(1): 108650
    miRNA-194-3p represses NF-κB in gliomas to attenuate iPSC genes and proneural to mesenchymal transition.
    John Ryan Jacob, Rajbir Singh, Masa Okamoto, Arnab Chakravarti, Kamalakannan Palanichamy.
      Severe tumor heterogeneity drives the aggressive and treatment refractory nature of glioblastomas (GBMs). While limiting GBM heterogeneity offers promising therapeutic potential, the underlying mechanisms that regulate GBM plasticity remain poorly understood. We utilized 14 patient-derived and four commercially available cell lines to uncover miR-194-3p as a key epigenetic determinant of stemness and transcriptional subtype in GBM. We demonstrate that miR-194-3p degrades TAB2, an important mediator of NF-κB activity, decreasing NF-κB transcriptional activity. The loss in NF-κB activity following miR-194-3p overexpression or TAB2 silencing decreased expression of induced pluripotent stem cell (iPSC) genes, inhibited the oncogenic IL-6/STAT3 signaling axis, suppressed the mesenchymal transcriptional subtype in relation to the proneural subtype, and induced differentiation from the glioma stem cell (GSC) to monolayer (ML) phenotype. miR-194-3p/TAB2/NF-κB signaling axis acts as an epigenetic switch that regulates GBM plasticity and targeting this signaling axis represents a potential strategy to limit transcriptional heterogeneity in GBMs.
    Keywords:  Cancer; Molecular neuroscience; Neuroscience; Stem cells research
    DOI:  https://doi.org/10.1016/j.isci.2023.108650
  9. Cell. 2024 Jan 18. pii: S0092-8674(23)01394-6. [Epub ahead of print]187(2): 271-273
    A holistic view of the malignant organism we call glioblastoma.
    Salma Baig, Frank Winkler.
      Tumors are not simply a chaotic mass of mutated cells but can follow complex organizational principles, including in space. In this issue of Cell, Mathur and colleagues reconstruct a 3D genomic, epigenomic, and transcriptomic spatial cartograph of glioblastoma, offering a "whole-tumor" perspective with patterns of clonal expansion that are embedded in neurodevelopmental hierarchy.
    DOI:  https://doi.org/10.1016/j.cell.2023.12.021
  10. Neuro Oncol. 2024 Jan 14. pii: noad247. [Epub ahead of print]
    Treatment-associated imaging changes in newly diagnosed MGMT promoter-methylated glioblastoma undergoing chemoradiation with or without cilengitide.
    Christina Maria Flies, Michel Friedrich, Philipp Lohmann, Karin Alida van Garderen, Marion Smits, Joerg-Christian Tonn, Michael Weller, Norbert Galldiks, Tom Jan Snijders.
       BACKGROUND: Radiological progression may originate from progressive disease (PD) or pseudoprogression/treatment-associated changes. We assessed radiological progression in MGMT promoter-methylated glioblastoma treated with standard-of-care chemoradiotherapy with or without the integrin inhibitor cilengitide according to the modified RANO criteria of 2017.
    METHODS: Patients with ≥3 follow-up MRIs were included. Preliminary PD was defined as a ≥25% increase of the sum of products of perpendicular diameters (SPD) of a new or increasing lesion compared to baseline. PD required a second ≥25% increase of the SPD. Treatment-associated changes required stable or regressing disease after preliminary PD.
    RESULTS: Of the 424 evaluable patients, 221 patients (52%) were randomized into the cilengitide, and 203 patients (48%) into the control arm. After chemoradiation with or without cilengitide, preliminary PD occurred in 274 patients (65%) during available follow-up, and 88 of these patients (32%) had treatment-associated changes, whereas 67 patients (25%) had PD. The remaining 119 patients (43%) had no further follow-up after preliminary PD. Treatment-associated changes were more common in the cilengitide arm than in the standard-of-care arm (24% vs. 17%; relative risk, 1.3; 95% confidence interval, 1.004-1.795; p=0.047). Treatment-associated changes occurred mainly during the first six months after RT (54% after three months vs. 13% after six months).
    CONCLUSION: With the modified RANO criteria, the rate of treatment-associated changes was low compared to previous studies in MGMT promoter-methylated glioblastoma. This rate was higher after cilengitide compared to standard-of-care treatment. Confirmatory scans, as recommended in the modified RANO criteria, were not always available reflecting current clinical practice.
    Keywords:  glioma; modified RANO criteria; pseudoprogression; temozolomide
    DOI:  https://doi.org/10.1093/neuonc/noad247
  11. Res Sq. 2023 Dec 28. pii: rs.3.rs-3793353. [Epub ahead of print]
    Enrichment of a neutrophil-like monocyte transcriptional state in glioblastoma myeloid suppressor cells.
    John Wiencke, Emily Nissen, Devin Koestler, Stanley Tamaki, Courtney Tamaki, Helen Hansen, Gayathri Warrier, Sara Hadad, Lucie McCoy, Terri Rice, Jennifer Clarke, Jennie Taylor, Lucas Salas, Brock Christensen, Karl Kelsey, Rondi Butler, Annette Molinaro.
      Glioblastomas (GBM) are lethal central nervous system cancers associated with tumor and systemic immunosuppression. Heterogeneous monocyte myeloid-derived suppressor cells (M-MDSC) are implicated in the altered immune response in GBM, but M-MDSC ontogeny and definitive phenotypic markers are unknown. Using single-cell transcriptomics, we revealed heterogeneity in blood M-MDSC from GBM subjects and an enrichment in a transcriptional state reminiscent of neutrophil-like monocytes (NeuMo), a newly described pathway of monopoiesis in mice. Human NeuMo gene expression and Neu-like deconvolution fraction algorithms were created to quantitate the enrichment of this transcriptional state in GBM subjects. NeuMo populations were also observed in M-MDSCs from lung and head and neck cancer subjects. Dexamethasone (DEX) and prednisone exposures increased the usage of Neu-like states, which were inversely associated with tumor purity and survival in isocitrate dehydrogenase wildtype (IDH WT) gliomas. Anti-inflammatory ZC3HA12/Regnase-1 transcripts were highly correlated with NeuMo expression in tumors and in blood M-MDSC from GBM, lung, and head and neck cancer subjects. Additional novel transcripts of immune-modulating proteins were identified. Collectively, these findings provide a framework for understanding the heterogeneity of M-MDSCs in GBM as cells with different clonal histories and may reshape approaches to study and therapeutically target these cells.
    DOI:  https://doi.org/10.21203/rs.3.rs-3793353/v1
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