bims-malgli Biomed News
on Biology of malignant gliomas
Issue of 2023‒06‒25
twelve papers selected by
Oltea Sampetrean
Keio University
  1. A prognostic matrix code defines functional glioblastoma phenotypes and niches.
  2. Chimeric antigen receptor (CAR) T cell-based targeting of CD317 as a novel immunotherapeutic strategy against glioblastoma.
  3. Individual glioblastoma cells harbor both proliferative and invasive capabilities during tumor progression.
  4. Blood-brain barrier disruption defines the extracellular metabolome of live human high-grade gliomas.
  5. Glioblastoma extracellular vesicles influence glial cell hyaluronic acid deposition to promote invasiveness.
  6. Mitoepigenetics and gliomas: epigenetic alterations to mitochondrial DNA and nuclear DNA alter mtDNA expression and contribute to glioma pathogenicity.
  7. Characterization and Optimization of the Tumor Microenvironment in Patient-Derived Organotypic Slices and Organoid Models of Glioblastoma.
  8. Hemizygous CDKN2A deletion confers worse survival outcomes in IDHmut-noncodel gliomas.
  9. Leptomeningeal disease in histone-mutant gliomas.
  10. Controllability and Robustness of Functional and Structural Connectomic Networks in Glioma Patients.
  11. Diagnostic and therapeutic potential of circular RNA in brain tumors.
  12. Intraoperative MRI-Guided Resection Is Not Superior to 5-Aminolevulinic Acid Guidance in Newly Diagnosed Glioblastoma: A Prospective Controlled Multicenter Clinical Trial.
  1. bioRxiv. 2023 Jun 08. pii: 2023.06.06.543903. [Epub ahead of print]
    A prognostic matrix code defines functional glioblastoma phenotypes and niches.
    Monika Vishnoi, Zeynep Dereli, Zheng Yin, Elisabeth K Kong, Meric Kinali, Kisan Thapa, Ozgun Babur, Kyuson Yun, Nourhan Abdelfattah, Xubin Li, Behnaz Bozorgui, Robert C Rostomily, Anil Korkut.
      Interactions among tumor, immune and vascular niches play major roles in driving glioblastoma (GBM) malignancy and treatment responses. The composition, heterogeneity, and localization of extracellular core matrix proteins (CMPs) that mediate such interactions, however, are not well understood. Here, we characterize functional and clinical relevance of genes encoding CMPs in GBM at bulk, single cell, and spatial anatomical resolution. We identify a "matrix code" for genes encoding CMPs whose expression levels categorize GBM tumors into matrisome-high and matrisome-low groups that correlate with worse and better survival, respectively, of patients. The matrisome enrichment is associated with specific driver oncogenic alterations, mesenchymal state, infiltration of pro-tumor immune cells and immune checkpoint gene expression. Anatomical and single cell transcriptome analyses indicate that matrisome gene expression is enriched in vascular and leading edge/infiltrative anatomic structures that are known to harbor glioma stem cells driving GBM progression. Finally, we identified a 17-gene matrisome signature that retains and further refines the prognostic value of genes encoding CMPs and, importantly, potentially predicts responses to PD1 blockade in clinical trials for GBM. The matrisome gene expression profiles may provide biomarkers of functionally relevant GBM niches that contribute to mesenchymal-immune cross talk and patient stratification to optimize treatment responses.
    DOI:  https://doi.org/10.1101/2023.06.06.543903
  2. Neuro Oncol. 2023 Jun 19. pii: noad108. [Epub ahead of print]
    Chimeric antigen receptor (CAR) T cell-based targeting of CD317 as a novel immunotherapeutic strategy against glioblastoma.
    Lena Hänsch, Matthias Peipp, Maximilian Mastall, Danielle Villars, Renier Myburgh, Manuela Silginer, Tobias Weiss, Dorothee Gramatzki, Flavio Vasella, Markus G Manz, Michael Weller, Patrick Roth.
      BACKGROUND: Chimeric antigen receptor (CAR) T cell therapy has proven to be successful against hematological malignancies. However, exploiting CAR T cells to treat solid tumors is more challenging for various reasons including the lack of suitable target antigens. Here, we identify the transmembrane protein CD317 as a novel target antigen for CAR T cell therapy against glioblastoma, one of the most aggressive solid tumors.METHODS: CD317-targeting CAR T cells were generated by lentivirally transducing human T cells from healthy donors. The anti-glioma activity of CD317-CAR T cells towards various glioma cells was assessed in vitro in cell lysis assays. Subsequently, we determined the efficacy of CD317-CAR T cells to control tumor growth in vivo in clinically relevant mouse glioma models.
    RESULTS: We generated CD317-specific CAR T cells and demonstrate strong anti-tumor activity against several glioma cell lines as well as primary patient-derived cells with varying CD317 expression levels in vitro. A CRISPR/Cas9-mediated knockout of CD317 protected glioma cells from CAR T cell lysis, demonstrating the target specificity of the approach. Silencing of CD317 expression in T cells by RNA interference reduced fratricide of engineered T cells and further improved their effector function. Using orthotopic glioma mouse models, we demonstrate the antigen-specific anti-tumor activity of CD317-CAR T cells, which resulted in prolonged survival and cure of a fraction of CAR T cell-treated animals.
    CONCLUSIONS: These data reveal a promising role of CD317-CAR T cell therapy against glioblastoma, which warrants further evaluation to translate this immunotherapeutic strategy into clinical neuro-oncology.
    Keywords:  BST2; CAR T cell; adoptive immune cell transfer; glioma; immunotherapy
    DOI:  https://doi.org/10.1093/neuonc/noad108
  3. Neuro Oncol. 2023 Jun 19. pii: noad109. [Epub ahead of print]
    Individual glioblastoma cells harbor both proliferative and invasive capabilities during tumor progression.
    Miriam Ratliff, Kianush Karimian-Jazi, Dirk C Hoffmann, Laurèl Rauschenbach, Matthias Simon, Ling Hai, Henriette Mandelbaum, Marc C Schubert, Tobias Kessler, Stefanie Uhlig, Daniel Dominguez Azorin, Erik Jung, Matthias Osswald, Gergely Solecki, Máté E Maros, Varun Venkataramani, Martin Glas, Nima Etminan, Björn Scheffler, Wolfgang Wick, Frank Winkler.
      BACKGROUND: Glioblastomas are characterized by aggressive and infiltrative growth, and by striking heterogeneity. The aim of this study was to investigate whether tumor cell proliferation and invasion are interrelated, or rather distinct features of different cell populations.METHODS: Tumor cell invasion and proliferation was longitudinally determined in real time using 3D in vivo two-photon laser scanning microscopy over weeks. Glioblastoma cells expressed fluorescent markers that permitted the identification of their mitotic history or their cycling versus non-cycling cell state.
    RESULTS: Live reporter systems were established that allowed to dynamically determine the invasive behavior, and previous or actual proliferation of distinct glioblastoma cells, in different tumor regions and disease stages over time. Particularly invasive tumor cells that migrated far away from the main tumor mass, when followed over weeks, had a history of marked proliferation and maintained their proliferative capacity during brain colonization. Infiltrating cells showed fewer connections to the multicellular tumor cell network, a typical feature of gliomas. Once tumor cells colonized a new brain region, their phenotype progressively transitioned into tumor microtube-rich, interconnected, slower-cycling glioblastoma cells. Analysis of resected human glioblastomas confirmed a higher proliferative potential of tumor cells from the invasion zone.
    CONCLUSION: The detection of glioblastoma cells that harbor both particularly high proliferative and invasive capabilities during brain tumor progression provides valuable insights into the interrelatedness of proliferation and migration - two central traits of malignancy in glioma. This contributes to our understanding how the brain is efficiently colonized in this disease.
    Keywords:  Glioblastoma; cancer neuroscience; migration; proliferation; tumor microtubes (TMs)
    DOI:  https://doi.org/10.1093/neuonc/noad109
  4. Commun Biol. 2023 Jun 20. 6(1): 653
    Blood-brain barrier disruption defines the extracellular metabolome of live human high-grade gliomas.
    Cecile Riviere-Cazaux, Lucas P Carlstrom, Karishma Rajani, Amanda Munoz-Casabella, Masum Rahman, Ali Gharibi-Loron, Desmond A Brown, Kai J Miller, Jaclyn J White, Benjamin T Himes, Ignacio Jusue-Torres, Samar Ikram, Seth C Ransom, Renee Hirte, Ju-Hee Oh, William F Elmquist, Jann N Sarkaria, Rachael A Vaubel, Moses Rodriguez, Arthur E Warrington, Sani H Kizilbash, Terry C Burns.
      The extracellular microenvironment modulates glioma behaviour. It remains unknown if blood-brain barrier disruption merely reflects or functionally supports glioma aggressiveness. We utilised intra-operative microdialysis to sample the extracellular metabolome of radiographically diverse regions of gliomas and evaluated the global extracellular metabolome via ultra-performance liquid chromatography tandem mass spectrometry. Among 162 named metabolites, guanidinoacetate (GAA) was 126.32x higher in enhancing tumour than in adjacent brain. 48 additional metabolites were 2.05-10.18x more abundant in enhancing tumour than brain. With exception of GAA, and 2-hydroxyglutarate in IDH-mutant gliomas, differences between non-enhancing tumour and brain microdialysate were modest and less consistent. The enhancing, but not the non-enhancing glioma metabolome, was significantly enriched for plasma-associated metabolites largely comprising amino acids and carnitines. Our findings suggest that metabolite diffusion through a disrupted blood-brain barrier may largely define the enhancing extracellular glioma metabolome. Future studies will determine how the altered extracellular metabolome impacts glioma behaviour.
    DOI:  https://doi.org/10.1038/s42003-023-05035-2
  5. Neurooncol Adv. 2023 Jan-Dec;5(1):5(1): vdad067
    Glioblastoma extracellular vesicles influence glial cell hyaluronic acid deposition to promote invasiveness.
    Dominik Koessinger, David Novo, Anna Koessinger, America Campos, Jasmine Peters, Louise Dutton, Peggy Paschke, Désirée Zerbst, Madeleine Moore, Louise Mitchell, Matthew Neilson, Katrina Stevenson, Anthony Chalmers, Stephen Tait, Joanna Birch, Jim Norman.
      Background: Infiltration of glioblastoma (GBM) throughout the brain leads to its inevitable recurrence following standard-of-care treatments, such as surgical resection, chemo-, and radiotherapy. A deeper understanding of the mechanisms invoked by GBM to infiltrate the brain is needed to develop approaches to contain the disease and reduce recurrence. The aim of this study was to discover mechanisms through which extracellular vesicles (EVs) released by GBM influence the brain microenvironment to facilitate infiltration, and to determine how altered extracellular matrix (ECM) deposition by glial cells might contribute to this.Methods: CRISPR was used to delete genes, previously established to drive carcinoma invasiveness and EV production, from patient-derived primary and GBM cell lines. We purified and characterized EVs released by these cells, assessed their capacity to foster pro-migratory microenvironments in mouse brain slices, and evaluated the contribution made by astrocyte-derived ECM to this. Finally, we determined how CRISPR-mediated deletion of genes, which we had found to control EV-mediated communication between GBM cells and astrocytes, influenced GBM infiltration when orthotopically injected into CD1-nude mice.
    Results: GBM cells expressing a p53 mutant (p53R273H) with established pro-invasive gain-of-function release EVs containing a sialomucin, podocalyxin (PODXL), which encourages astrocytes to deposit ECM with increased levels of hyaluronic acid (HA). This HA-rich ECM, in turn, promotes migration of GBM cells. Consistently, CRISPR-mediated deletion of PODXL opposes infiltration of GBM in vivo.
    Conclusions: This work describes several key components of an EV-mediated mechanism though which GBM cells educate astrocytes to support infiltration of the surrounding healthy brain tissue.
    Keywords:  GBM; astrocytes; extracellular matrix; extracellular vesicles; invasion
    DOI:  https://doi.org/10.1093/noajnl/vdad067
  6. Front Neurol. 2023 ;14 1154753
    Mitoepigenetics and gliomas: epigenetic alterations to mitochondrial DNA and nuclear DNA alter mtDNA expression and contribute to glioma pathogenicity.
    Clare I Grady, Lisa M Walsh, John D Heiss.
      Epigenetic mechanisms allow cells to fine-tune gene expression in response to environmental stimuli. For decades, it has been known that mitochondria have genetic material. Still, only recently have studies shown that epigenetic factors regulate mitochondrial DNA (mtDNA) gene expression. Mitochondria regulate cellular proliferation, apoptosis, and energy metabolism, all critical areas of dysfunction in gliomas. Methylation of mtDNA, alterations in mtDNA packaging via mitochondrial transcription factor A (TFAM), and regulation of mtDNA transcription via the micro-RNAs (mir 23-b) and long noncoding RNAs [RNA mitochondrial RNA processing (RMRP)] have all been identified as contributing to glioma pathogenicity. Developing new interventions interfering with these pathways may improve glioma therapy.
    Keywords:  epigenetics; glioblastoma; glioma; methylation; mitochondria; mitoepigenetics; mtDNA; noncoding RNA
    DOI:  https://doi.org/10.3389/fneur.2023.1154753
  7. Cancers (Basel). 2023 May 10. pii: 2698. [Epub ahead of print]15(10):
    Characterization and Optimization of the Tumor Microenvironment in Patient-Derived Organotypic Slices and Organoid Models of Glioblastoma.
    Vera Nickl, Juliana Eck, Nicolas Goedert, Julian Hübner, Thomas Nerreter, Carsten Hagemann, Ralf-Ingo Ernestus, Tim Schulz, Robert Carl Nickl, Almuth Friederike Keßler, Mario Löhr, Andreas Rosenwald, Maria Breun, Camelia Maria Monoranu.
      While glioblastoma (GBM) is still challenging to treat, novel immunotherapeutic approaches have shown promising effects in preclinical settings. However, their clinical breakthrough is hampered by complex interactions of GBM with the tumor microenvironment (TME). Here, we present an analysis of TME composition in a patient-derived organoid model (PDO) as well as in organotypic slice cultures (OSC). To obtain a more realistic model for immunotherapeutic testing, we introduce an enhanced PDO model. We manufactured PDOs and OSCs from fresh tissue of GBM patients and analyzed the TME. Enhanced PDOs (ePDOs) were obtained via co-culture with PBMCs (peripheral blood mononuclear cells) and compared to normal PDOs (nPDOs) and PT (primary tissue). At first, we showed that TME was not sustained in PDOs after a short time of culture. In contrast, TME was largely maintained in OSCs. Unfortunately, OSCs can only be cultured for up to 9 days. Thus, we enhanced the TME in PDOs by co-culturing PDOs and PBMCs from healthy donors. These cellular TME patterns could be preserved until day 21. The ePDO approach could mirror the interaction of GBM, TME and immunotherapeutic agents and may consequently represent a realistic model for individual immunotherapeutic drug testing in the future.
    Keywords:  glioblastoma; organoids; slice culture; tumormicroenvironment
    DOI:  https://doi.org/10.3390/cancers15102698
  8. Neuro Oncol. 2023 Jun 17. pii: noad095. [Epub ahead of print]
    Hemizygous CDKN2A deletion confers worse survival outcomes in IDHmut-noncodel gliomas.
    Emre Kocakavuk, Kevin C Johnson, Thais S Sabedot, Hans Christian Reinhardt, Houtan Noushmehr, Roel G W Verhaak.
      
    Keywords:   CDKN2A ; IDH-mutant; astrocytoma; glioma; hemizygous deletion
    DOI:  https://doi.org/10.1093/neuonc/noad095
  9. Neurooncol Adv. 2023 Jan-Dec;5(1):5(1): vdad068
    Leptomeningeal disease in histone-mutant gliomas.
    Maria Diaz, Satshil Rana, Carlos Eduardo Silva Correia, Anne S Reiner, Andrew L Lin, Alexandra M Miller, Maya S Graham, Sofia Chudsky, Tejus A Bale, Marc Rosenblum, Matthias A Karajannis, Elena Pentsova.
      Background: The 2016 WHO classification described a subtype of midline gliomas harboring histone 3 (H3) K27M alterations, and the 2021 edition added a new subtype of hemispheric diffuse gliomas with H3 G34R/V mutations. The incidence and clinical behavior of leptomeningeal disease (LMD) in these patients is not well defined.Methods: Retrospective study of patients with H3-altered gliomas diagnosed from 01/2012 to 08/2021; histone mutations were identified through next-generation sequencing (NGS) of tumor biopsy and/or cerebrospinal fluid (CSF).
    Results: We identified 42 patients harboring H3 mutations (K27M mutations in 33 patients, G34R/V in 8, and both in one). Median age was 21 (4-70); 27 were male. LMD was diagnosed in 21/42 (50%) patients, corresponding to a 3-year cumulative incidence of 44.7% (95% confidence interval (CI): 26.1%-63.4%) for the K27-mutant group and a 1-year cumulative incidence of 37.5% in the G34-mutant group (95% CI: 0.01%-74.4%; no events after 1 year). Median time from tumor diagnosis to LMD was 12.9 months for H3-K27 patients and 5.6 months for H3-G34 patients. H3 mutation was detected in CSF in all patients with LMD who had NGS (8 H3-K27-mutant patients). In the H3-K27-mutant group, modeled risk of death was increased in patients who developed LMD (hazard ratio: 7.37, 95% CI: 2.98-18.23, P < .0001).
    Conclusions: In our cohort, 50% of patients developed LMD. Although further studies are needed, CSF ctDNA characterization may aid in identifying molecular tumor profiles in glioma patients with LMD, and neuroaxis imaging and CSF NGS should be considered for early LMD detection.
    Keywords:  cerebrospinal fluid; circulating tumor DNA; diffuse hemispheric glioma; diffuse midline histone mutations; glioma; leptomeningeal disease
    DOI:  https://doi.org/10.1093/noajnl/vdad068
  10. Cancers (Basel). 2023 May 11. pii: 2714. [Epub ahead of print]15(10):
    Controllability and Robustness of Functional and Structural Connectomic Networks in Glioma Patients.
    Anke Meyer-Baese, Kerstin Jütten, Uwe Meyer-Baese, Ali Moradi Amani, Hagen Malberg, Andreas Stadlbauer, Thomas Kinfe, Chuh-Hyoun Na.
      Previous studies suggest that the topological properties of structural and functional neural networks in glioma patients are altered beyond the tumor location. These alterations are due to the dynamic interactions with large-scale neural circuits. Understanding and describing these interactions may be an important step towards deciphering glioma disease evolution. In this study, we analyze structural and functional brain networks in terms of determining the correlation between network robustness and topological features regarding the default-mode network (DMN), comparing prognostically differing patient groups to healthy controls. We determine the driver nodes of these networks, which are receptive to outside signals, and the critical nodes as the most important elements for controllability since their removal will dramatically affect network controllability. Our results suggest that network controllability and robustness of the DMN is decreased in glioma patients. We found losses of driver and critical nodes in patients, especially in the prognostically less favorable IDH wildtype (IDHwt) patients, which might reflect lesion-induced network disintegration. On the other hand, topological shifts of driver and critical nodes, and even increases in the number of critical nodes, were observed mainly in IDH mutated (IDHmut) patients, which might relate to varying degrees of network plasticity accompanying the chronic disease course in some of the patients, depending on tumor growth dynamics. We hereby implement a novel approach for further exploring disease evolution in brain cancer under the aspects of neural network controllability and robustness in glioma patients.
    Keywords:  controllability; critical nodes; driver set; glioma; robustness; structural and functional connectomics
    DOI:  https://doi.org/10.3390/cancers15102714
  11. Neurooncol Adv. 2023 Jan-Dec;5(1):5(1): vdad063
    Diagnostic and therapeutic potential of circular RNA in brain tumors.
    Keisuke Katsushima, Kandarp Joshi, Ranjan J Perera.
      Circular RNAs (circRNAs) are a class of RNA with a stable cyclic structure. They are expressed in various tissues and cells with conserved, specific characteristics. CircRNAs have been found to play critical roles in a wide range of cellular processes by regulating gene expression at the epigenetic, transcriptional, and posttranscriptional levels. There is an accumulation of evidence on newly discovered circRNAs, their molecular interactions, and their roles in the development and progression of human brain tumors, including cell proliferation, cell apoptosis, invasion, and chemoresistance. Here we summarize the current state of knowledge of the circRNAs that have been implicated in brain tumor pathogenesis, particularly in gliomas and medulloblastomas. In providing a comprehensive overview of circRNA studies, we highlight how different circRNAs have oncogenic or tumor-suppressive roles in brain tumors, making them attractive therapeutic targets and biomarkers for personalized therapy and precision diagnostics. This review article discusses circRNAs' functional roles and the prospect of using them as diagnostic biomarkers and therapeutic targets in patients with brain tumors.
    Keywords:  circRNA; glioma; medulloblastoma; microRNA
    DOI:  https://doi.org/10.1093/noajnl/vdad063
  12. J Clin Oncol. 2023 Jun 19. JCO2201862
    Intraoperative MRI-Guided Resection Is Not Superior to 5-Aminolevulinic Acid Guidance in Newly Diagnosed Glioblastoma: A Prospective Controlled Multicenter Clinical Trial.
    Constantin Roder, Walter Stummer, Jan Coburger, Moritz Scherer, Patrick Haas, Christian von der Brelie, Marcel Alexander Kamp, Mario Löhr, Christina A Hamisch, Marco Skardelly, Torben Scholz, Stephanie Schipmann, Julian Rathert, Catrin Marlene Brand, Andrej Pala, Ulrike Ernemann, Florian Stockhammer, Rüdiger Gerlach, Paul Kremer, Roland Goldbrunner, Ralf-Ingo Ernestus, Michael Sabel, Veit Rohde, Ghazaleh Tabatabai, Peter Martus, Sotirios Bisdas, Oliver Ganslandt, Andreas Unterberg, Christian Rainer Wirtz, Marcos Tatagiba.
      PURPOSE: Prospective data suggested a superiority of intraoperative MRI (iMRI) over 5-aminolevulinic acid (5-ALA) for achieving complete resections of contrast enhancement in glioblastoma surgery. We investigated this hypothesis in a prospective clinical trial and correlated residual disease volumes with clinical outcome in newly diagnosed glioblastoma.METHODS: This is a prospective controlled multicenter parallel-group trial with two center-specific treatment arms (5-ALA and iMRI) and blinded evaluation. The primary end point was complete resection of contrast enhancement on early postoperative MRI. We assessed resectability and extent of resection by an independent blinded centralized review of preoperative and postoperative MRI with 1-mm slices. Secondary end points included progression-free survival (PFS) and overall survival (OS), patient-reported quality of life, and clinical parameters.
    RESULTS: We recruited 314 patients with newly diagnosed glioblastomas at 11 German centers. A total of 127 patients in the 5-ALA and 150 in the iMRI arm were analyzed in the as-treated analysis. Complete resections, defined as a residual tumor ≤0.175 cm³, were achieved in 90 patients (78%) in the 5-ALA and 115 (81%) in the iMRI arm (P = .79). Incision-suture times (P < .001) were significantly longer in the iMRI arm (316 v 215 [5-ALA] minutes). Median PFS and OS were comparable in both arms. The lack of any residual contrast enhancing tumor (0 cm³) was a significant favorable prognostic factor for PFS (P < .001) and OS (P = .048), especially in methylguanine-DNA-methyltransferase unmethylated tumors (P = .006).
    CONCLUSION: We could not confirm superiority of iMRI over 5-ALA for achieving complete resections. Neurosurgical interventions in newly diagnosed glioblastoma shall aim for safe complete resections with 0 cm³ contrast-enhancing residual disease, as any other residual tumor volume is a negative predictor for PFS and OS.
    DOI:  https://doi.org/10.1200/JCO.22.01862
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