bims-malgli Biomed News
on Biology of malignant gliomas
Issue of 2024–12–01
eleven papers selected by
Oltea Sampetrean, Keio University
  1. Modulation of the Immune Environment in Glioblastoma by the Gut Microbiota.
  2. Functional profiling of murine glioma models highlights targetable immune evasion phenotypes.
  3. Glioblastoma Drives Protease-Independent Extracellular Matrix Invasion of Microglia.
  4. Homozygous CDKN2A/B deletions in low- and high-grade glioma: a meta-analysis of individual patient data and predictive values of p16 immunohistochemistry testing.
  5. Cell migration simulator-based biomarkers for glioblastoma.
  6. GNAO1 overexpression promotes neural differentiation of glioma stem-like cells and reduces tumorigenicity through TRIM21/CREB/HES1 axis.
  7. Canonical Amplifications and CDKN2A/B Loss Refine IDH1/2-mutant Astrocytoma Prognosis.
  8. Human single cell RNA-sequencing reveals a targetable CD8+ exhausted T cell population that maintains mouse low-grade glioma growth.
  9. Transcription factors ASCL1 and OLIG2 drive glioblastoma initiation and co-regulate tumor cell types and migration.
  10. γ-Glutamyl transpeptidase-activable nanoprobe crosses the blood-brain barrier for immuno-sonodynamic therapy of glioma.
  11. Current and Future Roles of Chimeric Antigen Receptor T-Cell Therapy in Neurology: A Review.
  1. Biomedicines. 2024 Oct 23. pii: 2429. [Epub ahead of print]12(11):
    Modulation of the Immune Environment in Glioblastoma by the Gut Microbiota.
    George B H Green, Alexis N Cox-Holmes, Anna Claire E Potier, Gillian H Marlow, Braden C McFarland.
      Studies increasingly support the role of the gut microbiota in glioma development and treatment, although the exact mechanisms remain unclear. Research indicates that the gut microbiota can influence glioma progression, response to therapies, and the effectiveness of treatments like immunotherapy, with certain microbial compositions being linked to better outcomes. Additionally, the gut microbiota impacts the tumor microenvironment, affecting both tumor growth and the response to treatment. This review will explore glioma, the gut microbiota, and how their interaction shapes glioma development and therapy responses. Additionally, this review examines the influence of gut microbiota metabolites, such as short-chain fatty acids (SCFAs) and tryptophan, on glioma development and treatment. It also explores gut microbiome signaling via pattern recognition receptors, and the role of molecular mimicry between microbial and tumor antigens in glioblastoma, and if these interactions affect glioma development and treatment.
    Keywords:  glioblastoma; glioma; microbiome
    DOI:  https://doi.org/10.3390/biomedicines12112429
  2. Acta Neuropathol. 2024 Nov 27. 148(1): 74
    Functional profiling of murine glioma models highlights targetable immune evasion phenotypes.
    Nicholas Mikolajewicz, Nazanin Tatari, Jiarun Wei, Neil Savage, Adrian Granda Farias, Vassil Dimitrov, David Chen, Zsolt Zador, Kuheli Dasgupta, Magali Aguilera-Uribe, Yu-Xi Xiao, Seon Yong Lee, Patricia Mero, Dillon McKenna, Chitra Venugopal, Kevin R Brown, Hong Han, Sheila Singh, Jason Moffat.
      Cancer-intrinsic immune evasion mechanisms and pleiotropy are a barrier to cancer immunotherapy. This is apparent in certain highly fatal cancers, including high-grade gliomas and glioblastomas (GBM). In this study, we evaluated two murine syngeneic glioma models (GL261 and CT2A) as preclinical models for human GBM using functional genetic screens, single-cell transcriptomics and machine learning approaches. Through CRISPR genome-wide co-culture killing screens with various immune cells (cytotoxic T cells, natural killer cells, and macrophages), we identified three key cancer-intrinsic evasion mechanisms: NFκB signaling, autophagy/endosome machinery, and chromatin remodeling. Additional fitness screens identified dependencies in murine gliomas that partially recapitulated those seen in human GBM (e.g., UFMylation). Our single-cell analyses showed that different glioma models exhibited distinct immune infiltration patterns and recapitulated key immune gene programs observed in human GBM, including hypoxia, interferon, and TNF signaling. Moreover, in vivo orthotopic tumor engraftment was associated with phenotypic shifts and changes in proliferative capacity, with murine tumors recapitulating the intratumoral heterogeneity observed in human GBM, exhibiting propensities for developmental- and mesenchymal-like phenotypes. Notably, we observed common transcription factors and cofactors shared with human GBM, including developmental (Nfia and Tcf4), mesenchymal (Prrx1 and Wwtr1), as well as cycling-associated genes (Bub3, Cenpa, Bard1, Brca1, and Mis18bp1). Perturbation of these genes led to reciprocal phenotypic shifts suggesting intrinsic feedback mechanisms that balance in vivo cellular states. Finally, we used a machine-learning approach to identify two distinct immune evasion gene programs, one of which represents a clinically-relevant phenotype and delineates a subpopulation of stem-like glioma cells that predict response to immune checkpoint inhibition in human patients. This comprehensive characterization helps bridge the gap between murine glioma models and human GBM, providing valuable insights for future therapeutic development.
    Keywords:  CT2A; GL261; Genome-wide CRISPR screen; Glioblastoma; Glioma; Human; Murine; scRNA-seq
    DOI:  https://doi.org/10.1007/s00401-024-02831-w
  3. bioRxiv. 2024 Nov 11. pii: 2024.11.08.622715. [Epub ahead of print]
    Glioblastoma Drives Protease-Independent Extracellular Matrix Invasion of Microglia.
    Chia-Wen Chang, Ashwin Bale, Rohit Bhargava, Brendan A C Harley.
      Glioblastoma (GBM) is the most common and lethal form of primary brain cancer. Microglia infiltration into the tumor microenvironment is associated with immunosuppression and poor prognosis. Improved physicochemical understanding of microglia activation and invasion may provide novel GBM therapeutic strategies essential for improving long-term treatment efficacy. Here, we combine microfluidic systems with 3-D collagen hydrogels to systematically investigate microglia activation, invasion, contractility and cytokine secretion in response of GBM-microglia crosstalk. GBM inflammatory biomolecules significantly promote activation and 3D invasion of microglia. Interestingly, microglia invasion is not significantly affected by inhibitors of MMP activity or cellular glycolysis. In contrast, ROCK-pathway inhibition significantly impedes microglia invasion. Infrared microscopy analyses show that GBM co-culture does not significantly alter microglia lipid content. Further, GBM conditioned media resulted in significantly increased collagen hydrogel contraction, suggesting the importance of microglia contractility to physically remodel the local extracellular matrix (ECM). We also identify a panel of soluble proteins that may contribute to microglia chemotaxis, such as TIMP-1 and CXCL12. Taken together, this study suggests that the presence of GBM cells can enhance microglia invasion via increased cellular contractility, independent of MMP activity and cellular glycolysis.
    DOI:  https://doi.org/10.1101/2024.11.08.622715
  4. Acta Neuropathol Commun. 2024 Nov 26. 12(1): 180
    Homozygous CDKN2A/B deletions in low- and high-grade glioma: a meta-analysis of individual patient data and predictive values of p16 immunohistochemistry testing.
    Darius Noack, Johannes Wach, Alonso Barrantes-Freer, Nils H Nicolay, Erdem Güresir, Clemens Seidel.
      CDKN2A/B deletions are prognostically relevant in low- and high-grade gliomas. Data on this is derived from heterogeneous series, an accurate estimation of survival risk from homozygous CDKN2A/B deletion is missing. Besides genetic testing, p16-immunohistochemistry (IHC) as a less cost intensive means for indirect detection of CDKN2A/B alterations is possible but not validated in larger datasets. The present meta-analysis aimed to (1) reconstruct individual patient data (IPD) and estimate overall survival (OS) stratified by CDKN2A/B status from all literature and to (2) determine accuracy of p16 testing for CDKNA2/B detection from published studies. For survival analysis according to CDKN2A/B status 460 records were screened, four articles with 714 participants were included. In IDH-wildtype (IDH-wt) gliomas, 57.07% harbored the deletion compared to 9.76% in IDH-mutant (IDH-mut) gliomas. Median OS of patients with IDH-wt gliomas and homozygous CDKN2A/B deletion was 13.0 months compared to 18.0 months with non-deleted CDKN2A/B (p = 0.014, Log-Rank). With homozygous deletion of CDKN2A/B the risk of death was increased by 1.5 (95%-CI 1.1-2.1). Median OS in patients with IDH-mut gliomas without CDKN2A/B deletion was 92.0 months compared to 40.0 months with CDKN2A/B deletion (p < 0.001, Log-Rank). CDKN2A/B deletions were associated with a significantly shorter OS (HR = 3.2; 95%-CI 2.2-5.5). For p16 IHC analysis, 10 eligible studies with 1087 examined samples were included. The cut-off for retention differed between the studies. In 588/662 p16 retained cases CDKN2A/B deletions was not detected, implying a negative predictive value (NPV) of p16 staining of 88.8%. Conversely, 279/425 p16 absent cases showed a CDKN2A/B deletion resulting in a positive predictive value (PPV) of 65.6%. Sensitivity of p16 staining for CDKN2A/B detection was 79.0%, specificity 80.1%. Highest diagnostic accuracy of p16 IHC was reached with a cut-off of > 5% and within IDH-mut glioma.
    Keywords:  CDKN2A/B; Glioma; Individual patient data; Meta-analysis; Overall survival; p16
    DOI:  https://doi.org/10.1186/s40478-024-01889-7
  5. Neurooncol Adv. 2024 Jan-Dec;6(1):6(1): vdae184
    Cell migration simulator-based biomarkers for glioblastoma.
    Jay Hou, Mariah McMahon, Tyler Jubenville, Jann N Sarkaria, Clark C Chen, David J Odde.
       Background: Glioblastoma is the most aggressive malignant brain tumor with poor survival due to its invasive nature driven by cell migration, with unclear linkage to transcriptomic information. The aim of this study was to develop a physics-based framework connecting to transcriptomics to predict patient-specific glioblastoma cell migration.
    Methods and Results: We applied a physics-based motor-clutch model, a cell migration simulator (CMS), to parameterize the migration of glioblastoma cells and define physical biomarkers on a patient-by-patient basis. We reduced the 11-dimensional parameter space of the CMS into 3 principal physical parameters that govern cell migration: motor number-describing myosin II activity, clutch number-describing adhesion level, and F-actin polymerization rate. Experimentally, we found that glioblastoma patient-derived (xenograft) cell lines across mesenchymal (MES), proneural, and classical subtypes and 2 institutions (N = 13 patients) had optimal motility and traction force on stiffnesses around 9.3 kPa, with otherwise heterogeneous and uncorrelated motility, traction, and F-actin flow. By contrast, with the CMS parameterization, we found that glioblastoma cells consistently had balanced motor/clutch ratios to enable effective migration and that MES cells had higher actin polymerization rates resulting in higher motility. The CMS also predicted differential sensitivity to cytoskeletal drugs between patients. Finally, we identified 18 genes that correlated with the physical parameters, suggesting transcriptomic data alone could potentially predict the mechanics and speed of glioblastoma cell migration.
    Conclusions: We describe a general physics-based framework for parameterizing individual glioblastoma patients and connecting to clinical transcriptomic data that can potentially be used to develop patient-specific anti-migratory therapeutic strategies.
    Keywords:  biophysical modeling; cell migration; glioblastoma subtypes; motor-clutch model; patient-derived cell lines
    DOI:  https://doi.org/10.1093/noajnl/vdae184
  6. Oncogene. 2024 Nov 23.
    GNAO1 overexpression promotes neural differentiation of glioma stem-like cells and reduces tumorigenicity through TRIM21/CREB/HES1 axis.
    Bowen Sun, Ge Wang, Guoyu Chen, Yingwen Zhang, Ru Yang, He Hua, Yanxin Li, Haizhong Feng.
      Inducing tumor cell differentiation is a promising strategy for treating malignant cancers, including glioma, yet the critical regulator(s) underlying glioma cell differentiation is poorly understood. Here, we identify G Protein Subunit Alpha O1 (GNAO1) as a critical regulator of neural differentiation of glioma stem-like cells (GSCs). GNAO1 expression was lower in gliomas than in normal neuronal tissues and high expression of GNAO1 correlated with a better prognosis. GNAO1 overexpression markedly promoted neural differentiation of GSCs, leading to decreased cell proliferation and colony formation. Mechanistically, GNAO1 recruited TRIM21 and facilitated TRIM21-mediated ubiquitination. This ubiquitination resulted in the degradation of CREB and further reduced p300-mediated H3K27ac levels of the HES1 promoter. As a result, GNAO1 overexpression downregulated HES1 expression, which reinforced neuronal differentiation. In addition, knockdown of METTL3, a key writer of the N6-methyladenosine (m6A), enhanced GNAO1 mRNA stability. Treatment with GNAO1 adenovirus increased neuronal differentiation of tumor cells and reduced tumor cell proliferation in orthotopic GSC xenografts and temozolomide further enhanced GNAO1 adenovirus effects, resulting in extended animal survival. Our study presents that engineering GNAO1 overexpression-inducing neural differentiation of GSCs is a potential therapy strategy via synergistic inhibition of malignant proliferation and chemotherapy resistance.
    DOI:  https://doi.org/10.1038/s41388-024-03234-7
  7. Neuro Oncol. 2024 Nov 25. pii: noae258. [Epub ahead of print]
    Canonical Amplifications and CDKN2A/B Loss Refine IDH1/2-mutant Astrocytoma Prognosis.
    Hia S Ghosh, Ruchit V Patel, Elizabeth B Claus, L Nicolas Gonzalez Castro, Patrick Y Wen, Keith L Ligon, David M Meredith, Wenya Linda Bi.
       BACKGROUND: Molecular features have been incorporated alongside histologic criteria to improve glioma diagnostics and prognostication. CDKN2A/B homozygous-loss associates with worse survival in IDH1/2-mutant astrocytomas (IDHmut-astrocytomas), the presence of which denotes grade 4 tumor independent of histologic features. However, no molecular features distinguish survival amongst histologically-defined grade 2 and 3 IDHmut-astrocytomas.
    METHODS: We assembled a cohort of patients ≥19 years old diagnosed with an IDHmut-astrocytoma between 1989-2020 from public datasets and several academic medical centers. Multivariate modeling and unbiased clustering were used to stratify risk.
    RESULTS: We identified 998 IDHmut-astrocytoma patients (41.5% female; 85.6% white). Tumor grade, CDKN2A/B loss, and/or ≥1 focal amplification was associated with reduced survival. Grade 2/3 patients with intact CDKN2A/B and no focal amplifications survived the longest (OS 205.7 months). Survival for grade 2/3 cases with either CDKN2A/B hemizygous-loss or focal amplifications (80.4, 88.7 months respectively) did not differ significantly from grade 4 cases with intact CDKN2A/B and no amplifications (91.5 months, p=0.93). Grade 4 patients with either hemizygous or homozygous loss of CDKN2A/B had the shortest survival (OS 31.9, 32.5 months respectively), followed by grade 4 cases with intact CDKN2A/B and focal gene amplifications (OS 55.9 months). Integrating CDKN2A/B status and amplifications alongside histopathologic grade refined overall survival prediction. Unbiased clustering revealed 9 distinct molecular profiles, with differential survival. IDHmut-astrocytomas with any CDKN2A/B-loss clustered together, regardless of grade, and exhibited the poorest outcomes.
    CONCLUSIONS: Combining CDKN2A/B hemizygous-loss and focal gene amplifications reveals a group of IDHmut-astrocytoma patients with intermediate prognosis, refining IDHmut-astrocytoma classification.
    Keywords:   CDKN2A/B loss; IDH1/2-mutant astrocytoma; focal amplification; glioma; molecular risk stratification
    DOI:  https://doi.org/10.1093/neuonc/noae258
  8. Nat Commun. 2024 Nov 28. 15(1): 10312
    Human single cell RNA-sequencing reveals a targetable CD8+ exhausted T cell population that maintains mouse low-grade glioma growth.
    Rasha Barakat, Jit Chatterjee, Rui Mu, Xuanhe Qi, Xingxing Gu, Igor Smirnov, Olivia Cobb, Karen Gao, Angelica Barnes, Jonathan Kipnis, David H Gutmann.
      In solid cancers, T cells typically function as cytotoxic effectors to limit tumor growth, prompting therapies that capitalize upon this antineoplastic property (immune checkpoint inhibition; ICI). Unfortunately, ICI treatments have been largely ineffective for high-grade brain tumors (gliomas; HGGs). Leveraging several single-cell RNA sequencing datasets, we report greater CD8+ exhausted T cells in human pediatric low-grade gliomas (LGGs) relative to adult and pediatric HGGs. Using several preclinical mouse LGG models (Nf1-OPG mice), we show that these PD1+/TIGIT+ CD8+ exhausted T cells are restricted to the tumor tissue, where they express paracrine factors necessary for OPG growth. Importantly, ICI treatments with α-PD1 and α-TIGIT antibodies attenuate Nf1-OPG tumor proliferation through suppression of two cytokine (Ccl4 and TGFβ)-mediated mechanisms, rather than by T cell-mediated cytotoxicity, as well as suppress monocyte-controlled T cell chemotaxis. Collectively, these findings establish a previously unrecognized function for CD8+ exhausted T cells as specialized regulators of LGG maintenance.
    DOI:  https://doi.org/10.1038/s41467-024-54569-4
  9. Nat Commun. 2024 Nov 28. 15(1): 10363
    Transcription factors ASCL1 and OLIG2 drive glioblastoma initiation and co-regulate tumor cell types and migration.
    Bianca L Myers, Kathryn J Brayer, Luis E Paez-Beltran, Estrella Villicana, Matthew S Keith, Hideaki Suzuki, Jessie Newville, Rebekka H Anderson, Yunee Lo, Conner M Mertz, Rahul K Kollipara, Mark D Borromeo, Q Richard Lu, Robert M Bachoo, Jane E Johnson, Tou Yia Vue.
      Glioblastomas (GBMs) are highly aggressive, infiltrative, and heterogeneous brain tumors driven by complex genetic alterations. The basic-helix-loop-helix (bHLH) transcription factors ASCL1 and OLIG2 are dynamically co-expressed in GBMs; however, their combinatorial roles in regulating the plasticity and heterogeneity of GBM cells are unclear. Here, we show that induction of somatic mutations in subventricular zone (SVZ) progenitor cells leads to the dysregulation of ASCL1 and OLIG2, which then function redundantly and are required for brain tumor formation in a mouse model of GBM. Subsequently, the binding of ASCL1 and OLIG2 to each other's loci and to downstream target genes then determines the cell types and degree of migration of tumor cells. Single-cell RNA sequencing (scRNA-seq) reveals that a high level of ASCL1 is key in specifying highly migratory neural stem cell (NSC)/astrocyte-like tumor cell types, which are marked by upregulation of ribosomal protein, oxidative phosphorylation, cancer metastasis, and therapeutic resistance genes.
    DOI:  https://doi.org/10.1038/s41467-024-54750-9
  10. Nat Commun. 2024 Nov 29. 15(1): 10418
    γ-Glutamyl transpeptidase-activable nanoprobe crosses the blood-brain barrier for immuno-sonodynamic therapy of glioma.
    Bo Li, Gengjia Chen, Huihai Zhong, Tan Li, Minzhao Lin, Huiye Wei, Qiaoyun Zhang, Qi Chen, Jinsheng Huang, Xintao Shuai.
      Effective treatment against glioma remains challenging nowadays because the protective blood-brain barrier (BBB) impedes drug penetration into brain and the limited efficacy of conventional chemotherapy. While strong positively charged nanoparticles have good permeability through the BBB, they often come with the caveat of cationic toxicity to healthy tissues and organs during blood circulation. Here we show a neutrally charged nanoprobe with a surface decorated with γ-glutamyl moieties that can be cleaved by γ-glutamyl transpeptidase, an enzyme overexpressed on brain capillaries. Upon the cleavage, positively charged primary amines are generated, facilitating the effective crossing of the nanoprobe through BBB via the adsorption-mediated transcytosis pathway, while avoiding the caveat of cationic toxicity. In addition, when reaching the acidic tumor microenvironment, the nanoprobe co-encapsulating sonosensitizer and immune agonist swells, which results in an accelerated drug release under ultrasound irradiation to induce a combined immune response, ultimately leading to a robust anticancer effect. Overall, we report an effective drug delivery nanoplatform across the BBB for an enhanced therapy of glioma.
    DOI:  https://doi.org/10.1038/s41467-024-54382-z
  11. JAMA Neurol. 2024 Nov 25.
    Current and Future Roles of Chimeric Antigen Receptor T-Cell Therapy in Neurology: A Review.
    Fatme Seval Ismail, Marco Gallus, Sven G Meuth, Hideho Okada, Hans-Peter Hartung, Nico Melzer.
       Importance: Advancements in molecular engineering have facilitated the creation of engineered T cells that express synthetic receptors, termed chimeric antigen receptors (CARs). This is promising not only in cancer treatment but also in addressing a spectrum of other conditions. This review provides a comprehensive overview of the current approaches and future potential of CAR T-cell therapy in the field of neurology, particularly for primary brain tumors and autoimmune neurological disorders.
    Observations: CAR T-cell therapy for glioblastoma is promising; however, first-in-human trials did not yield significant success or showed only limited success in a subset of patients. To date, the efficacy of CAR T-cell therapies has been demonstrated in animal models of multiple sclerosis, but larger human studies to corroborate the efficacy remain pending. CAR T cells showed efficacy in treatment of patients with relapsed or refractory aquaporin 4-immunoglobulin G-seropositive neuromyelitis optica spectrum disorders. Further studies with larger patient populations are needed to confirm these results. Success was reported also for treatment of cases with generalized myasthenia gravis using CAR T cells. Chimeric autoantibody receptor T cells, representing a modified form of CAR T cells directed against autoreactive B cells secreting autoantibodies, were used to selectively target autoreactive anti-N-methyl-d-aspartate B cells under in vitro and in vivo conditions, providing the basis for human studies and application to other types of autoimmune encephalitis associated with neuronal or glial antibodies.
    Conclusions and Relevance: CAR T cells herald a new era in the therapeutic landscape of neurological disorders. While their application in solid tumors, such as glioblastoma, has not universally yielded robust success, emerging innovative strategies show promise, and there is optimism for their effectiveness in certain autoimmune neurological disorders.
    DOI:  https://doi.org/10.1001/jamaneurol.2024.3818
This page is being maintained by Thomas Krichel. It was last updated on 2024‒12‒01 at 15:00.