bims-malgli Biomed News
on Biology of malignant gliomas
Issue of 2021–07–04
twenty-one papers selected by
Oltea Sampetrean, Keio University
  1. Inhibiting DNA-PK induces glioma stem cell differentiation and sensitizes glioblastoma to radiation in mice.
  2. Neuro-Signals from Gut Microbiota: Perspectives for Brain Glioma.
  3. SLIT2/ROBO signaling in tumor-associated microglia/macrophages drives glioblastoma immunosuppression and vascular dysmorphia.
  4. One-Carbon Metabolism Associated Vulnerabilities in Glioblastoma: A Review.
  5. Spatial progression and molecular heterogeneity of IDH-mutant glioblastoma determined by DNA methylation-based mapping.
  6. Advances in Chemokine Signaling Pathways as Therapeutic Targets in Glioblastoma.
  7. Friend or Foe: Paradoxical Roles of Autophagy in Gliomagenesis.
  8. Molecular diagnostics helps to identify distinct subgroups of spinal astrocytomas.
  9. Resolution of tissue signatures of therapy response in patients with recurrent GBM treated with neoadjuvant anti-PD1.
  10. High-Resolution Cartography of the Transcriptome and Methylome Landscapes of Diffuse Gliomas.
  11. Neural stem cell delivery of an oncolytic adenovirus in newly diagnosed malignant glioma: a first-in-human, phase 1, dose-escalation trial.
  12. BOLD Asynchrony Elucidates Tumor Burden in IDH-Mutated Gliomas.
  13. Association of Circadian Clock Gene Expression with Glioma Tumor Microenvironment and Patient Survival.
  14. Dual Role of Integrin Alpha-6 in Glioblastoma: Supporting Stemness in Proneural Stem-Like Cells While Inducing Radioresistance in Mesenchymal Stem-Like Cells.
  15. The Current Landscape of Oncolytic Herpes Simplex Viruses as Novel Therapies for Brain Malignancies.
  16. A delicate initiation: Lipolysis of lipid droplets fuels glioblastoma.
  17. PRRX1 induced by BMP signaling decreases tumorigenesis by epigenetically regulating glioma-initiating cell properties via DNA methyltransferase 3A.
  18. Dual role of WNT5A in promoting endothelial differentiation of glioma stem cells and angiogenesis of glioma derived endothelial cells.
  19. Patient-derived models recapitulate heterogeneity of molecular signatures and drug response in pediatric high-grade glioma.
  20. The 2021 WHO Classification of Tumors of the Central Nervous System: a summary.
  21. Hitchhiking to brain tumours: stem cell delivery of oncolytic viruses.
  1. Sci Transl Med. 2021 Jun 30. pii: eabc7275. [Epub ahead of print]13(600):
    Inhibiting DNA-PK induces glioma stem cell differentiation and sensitizes glioblastoma to radiation in mice.
    Xiaoguang Fang, Zhi Huang, Kui Zhai, Qian Huang, Weiwei Tao, Leo Kim, Qiulian Wu, Alexandru Almasan, Jennifer S Yu, Xiaoxia Li, George R Stark, Jeremy N Rich, Shideng Bao.
      Glioblastoma (GBM), a lethal primary brain tumor, contains glioma stem cells (GSCs) that promote malignant progression and therapeutic resistance. SOX2 is a core transcription factor that maintains the properties of stem cells, including GSCs, but mechanisms associated with posttranslational SOX2 regulation in GSCs remain elusive. Here, we report that DNA-dependent protein kinase (DNA-PK) governs SOX2 stability through phosphorylation, resulting in GSC maintenance. Mass spectrometric analyses of SOX2-binding proteins showed that DNA-PK interacted with SOX2 in GSCs. The DNA-PK catalytic subunit (DNA-PKcs) was preferentially expressed in GSCs compared to matched non-stem cell tumor cells (NSTCs) isolated from patient-derived GBM xenografts. DNA-PKcs phosphorylated human SOX2 at S251, which stabilized SOX2 by preventing WWP2-mediated ubiquitination, thus promoting GSC maintenance. We then demonstrated that when the nuclear DNA of GSCs either in vitro or in GBM xenografts in mice was damaged by irradiation or treatment with etoposide, the DNA-PK complex dissociated from SOX2, which then interacted with WWP2, leading to SOX2 degradation and GSC differentiation. These results suggest that DNA-PKcs-mediated phosphorylation of S251 was critical for SOX2 stabilization and GSC maintenance. Pharmacological inhibition of DNA-PKcs with the DNA-PKcs inhibitor NU7441 reduced GSC tumorsphere formation in vitro and impaired growth of intracranial human GBM xenografts in mice as well as sensitized the GBM xenografts to radiotherapy. Our findings suggest that DNA-PK maintains GSCs in a stem cell state and that DNA damage triggers GSC differentiation through precise regulation of SOX2 stability, highlighting that DNA-PKcs has potential as a therapeutic target in glioblastoma.
    DOI:  https://doi.org/10.1126/scitranslmed.abc7275
  2. Cancers (Basel). 2021 Jun 04. pii: 2810. [Epub ahead of print]13(11):
    Neuro-Signals from Gut Microbiota: Perspectives for Brain Glioma.
    Giuseppina D'Alessandro, Clotilde Lauro, Deborah Quaglio, Francesca Ghirga, Bruno Botta, Flavia Trettel, Cristina Limatola.
      Glioblastoma (GBM) is the most aggressive form of glioma tumor in adult brain. Among the numerous factors responsible for GBM cell proliferation and invasion, neurotransmitters such as dopamine, serotonin and glutamate can play key roles. Studies performed in mice housed in germ-free (GF) conditions demonstrated the relevance of the gut-brain axis in a number of physiological and pathological conditions. The gut-brain communication is made possible by vagal/nervous and blood/lymphatic routes and pave the way for reciprocal modulation of functions. The gut microbiota produces and consumes a wide range of molecules, including neurotransmitters (dopamine, norepinephrine, serotonin, gamma-aminobutyric acid [GABA], and glutamate) that reach their cellular targets through the bloodstream. Growing evidence in animals suggests that modulation of these neurotransmitters by the microbiota impacts host neurophysiology and behavior, and affects neural cell progenitors and glial cells, along with having effects on tumor cell growth. In this review we propose a new perspective connecting neurotransmitter modulation by gut microbiota to glioma progression.
    Keywords:  cell proliferation; glioma; gut-brain axis; microbiota; neurotransmitters
    DOI:  https://doi.org/10.3390/cancers13112810
  3. J Clin Invest. 2021 Jun 29. pii: 141083. [Epub ahead of print]
    SLIT2/ROBO signaling in tumor-associated microglia/macrophages drives glioblastoma immunosuppression and vascular dysmorphia.
    Luiz H Geraldo, Yunling Xu, Laurent Jacob, Laurence Pibouin-Fragner, Rohit Rao, Nawal Maïssa, Maite Verreault, Nolwenn Lemaire, Camille Knosp, Corinne Lesaffre, Thomas Daubon, Joost Dejaegher, Lien Solie, Justine Rudewicz, Thomas Viel, Bertrand Tavitian, Steven De Vleeschouwer, Marc Sanson, Andreas Bikfalvi, Ahmed Idbaih, Qing Richard Lu, Flavia Rs Lima, Jean-Leon Thomas, Anne Eichmann, Thomas Mathivet.
      SLIT2 is a secreted polypeptide that guides migration of cells expressing ROBO1&2 receptors. Herein, we investigated SLIT2/ROBO signaling effects in gliomas. In patients with glioblastoma (GBM), SLIT2 expression increased with malignant progression and correlated with poor survival and immunosuppression. Knockdown of SLIT2 in mouse glioma cells and patient derived GBM xenografts reduced tumor growth and rendered tumors sensitive to immunotherapy. Tumor cell SLIT2 knockdown inhibited macrophage invasion and promoted a cytotoxic gene expression profile, which improved tumor vessel function and enhanced efficacy of chemotherapy and immunotherapy. Mechanistically, SLIT2 promoted microglia/macrophage chemotaxis and tumor-supportive polarization via ROBO1&2-mediated PI3Kgamma activation. Macrophage Robo1&2 deletion and systemic SLIT2 trap delivery mimicked SLIT2 knockdown effects on tumor growth and the tumor microenvironment (TME), revealing SLIT2 signaling through macrophage ROBOs as a potentially novel regulator of the GBM microenvironment and immunotherapeutic target for brain tumors.
    Keywords:  Brain cancer; Immunotherapy; Macrophages; Oncology; Vascular Biology
    DOI:  https://doi.org/10.1172/JCI141083
  4. Cancers (Basel). 2021 Jun 19. pii: 3067. [Epub ahead of print]13(12):
    One-Carbon Metabolism Associated Vulnerabilities in Glioblastoma: A Review.
    Kimia Ghannad-Zadeh, Sunit Das.
      Altered cell metabolism is a hallmark of cancer cell biology, and the adaptive metabolic strategies of cancer cells have been of recent interest to many groups. Metabolic reprogramming has been identified as a critical step in glial cell transformation, and the use of antimetabolites against glioblastoma has been investigated. One-carbon (1-C) metabolism and its associated biosynthetic pathways, particularly purine nucleotide synthesis, are critical for rapid proliferation and are altered in many cancers. Purine metabolism has also been identified as essential for glioma tumourigenesis. Additionally, alterations of 1-C-mediated purine synthesis have been identified as commonly present in brain tumour initiating cells (BTICs) and could serve as a phenotypic marker of cells responsible for tumour recurrence. Further research is required to elucidate mechanisms through which metabolic vulnerabilities may arise in BTICs and potential ways to therapeutically target these metabolic processes. This review aims to summarize the role of 1-C metabolism-associated vulnerabilities in glioblastoma tumourigenesis and progression and investigate the therapeutic potential of targeting this pathway in conjunction with other treatment strategies.
    Keywords:  de novo purine synthesis; glioblastoma; glioma; metabolic reprogramming; metabolic treatment; one-carbon metabolism
    DOI:  https://doi.org/10.3390/cancers13123067
  5. Acta Neuropathol Commun. 2021 Jun 30. 9(1): 120
    Spatial progression and molecular heterogeneity of IDH-mutant glioblastoma determined by DNA methylation-based mapping.
    James F Lyon, Varshini Vasudevaraja, Kanish Mirchia, Jamie M Walker, Robert J Corona, Lawrence S Chin, Ivy Tran, Matija Snuderl, Timothy E Richardson, Mariano S Viapiano.
      Glioblastoma (GBM) is the most common malignant primary central nervous system (CNS) neoplasm in adults, and has an almost universally poor prognosis. Recently, an emphasis on genetic and epigenetic profiling has revealed a number of molecular features useful in the diagnostic and prognostic classification of GBM, advancing our understanding of the underlying features that make these tumors so aggressive and providing the rationale for the creation of better targeted therapeutics. One such method, DNA methylation profiling, has recently emerged as an important technique for the classification of CNS tumors, with diagnostic accuracy in some cases surpassing traditional methods. However, how DNA methylation profiles change with the course of the disease remains less understood. Here, we present a case of a 30-year-old male with primary IDH-mutant GBM with widespread recurrence and death two years later. Using unsupervised hierarchical clustering of methylation probes, we created a phylogenetic map to trace the tumor path as it spread from the initial biopsy site throughout the right hemisphere, across the corpus callosum to the contralateral hemisphere, and into the brainstem. We identified molecular divergence between the right and left hemisphere GBM samples marked by distinct copy number profile alterations, alterations in specific methylation sites, and regional loss of MGMT promoter methylation, providing a potential mechanism for treatment resistance in this case. In summary, this case both highlights the molecular diversity in GBM, and illustrates a novel use for methylation profiling in establishing a phylogenetic profile to allow for spatial mapping of tumor progression.
    Keywords:  Astrocytoma; Copy number profiling; DNA methylation profiling; Glioblastoma; IDH-mutation; MGMT methylation
    DOI:  https://doi.org/10.1186/s40478-021-01221-7
  6. Cancers (Basel). 2021 Jun 15. pii: 2983. [Epub ahead of print]13(12):
    Advances in Chemokine Signaling Pathways as Therapeutic Targets in Glioblastoma.
    Ruth M Urbantat, Peter Vajkoczy, Susan Brandenburg.
      With a median patient survival of 15 months, glioblastoma (GBM) is still one of the deadliest malign tumors. Despite immense efforts, therapeutic regimens fail to prolong GBM patient overall survival due to various resistance mechanisms. Chemokine signaling as part of the tumor microenvironment plays a key role in gliomagenesis, proliferation, neovascularization, metastasis and tumor progression. In this review, we aimed to investigate novel therapeutic approaches targeting various chemokine axes, including CXCR2/CXCL2/IL-8, CXCR3/CXCL4/CXCL9/CXCL10, CXCR4/CXCR7/CXCL12, CXCR6/CXCL16, CCR2/CCL2, CCR5/CCL5 and CX3CR1/CX3CL1 in preclinical and clinical studies of GBM. We reviewed targeted therapies as single therapies, in combination with the standard of care, with antiangiogenic treatment as well as immunotherapy. We found that there are many antagonist-, antibody-, cell- and vaccine-based therapeutic approaches in preclinical and clinical studies. Furthermore, targeted therapies exerted their highest efficacy in combination with other established therapeutic applications. The novel chemokine-targeting therapies have mainly been examined in preclinical models. However, clinical applications are auspicious. Thus, it is crucial to broadly investigate the recently developed preclinical approaches. Promising preclinical applications should then be investigated in clinical studies to create new therapeutic regimens and to overcome therapy resistance to GBM treatment.
    Keywords:  GBM; antiangiogenic therapy; chemokine receptors; immunotherapy; targeted therapy
    DOI:  https://doi.org/10.3390/cancers13122983
  7. Cells. 2021 Jun 06. pii: 1411. [Epub ahead of print]10(6):
    Friend or Foe: Paradoxical Roles of Autophagy in Gliomagenesis.
    Don Carlo Ramos Batara, Moon-Chang Choi, Hyeon-Uk Shin, Hyunggee Kim, Sung-Hak Kim.
      Glioblastoma multiforme (GBM) is the most common and aggressive type of primary brain tumor in adults, with a poor median survival of approximately 15 months after diagnosis. Despite several decades of intensive research on its cancer biology, treatment for GBM remains a challenge. Autophagy, a fundamental homeostatic mechanism, is responsible for degrading and recycling damaged or defective cellular components. It plays a paradoxical role in GBM by either promoting or suppressing tumor growth depending on the cellular context. A thorough understanding of autophagy's pleiotropic roles is needed to develop potential therapeutic strategies for GBM. In this paper, we discussed molecular mechanisms and biphasic functions of autophagy in gliomagenesis. We also provided a summary of treatments for GBM, emphasizing the importance of autophagy as a promising molecular target for treating GBM.
    Keywords:  autophagy; glioblastoma multiforme; treatment
    DOI:  https://doi.org/10.3390/cells10061411
  8. Acta Neuropathol Commun. 2021 Jun 30. 9(1): 119
    Molecular diagnostics helps to identify distinct subgroups of spinal astrocytomas.
    Annamaria Biczok, Felix L Strübing, Julia M Eder, Rupert Egensperger, Oliver Schnell, Stefan Zausinger, Julia E Neumann, Jochen Herms, Joerg-Christian Tonn, Mario M Dorostkar.
      Primary spinal cord astrocytomas are rare, hence few data exist about the prognostic significance of molecular markers. Here we analyze a panel of molecular alterations in association with the clinical course. Histology and genome sequencing was performed in 26 spinal astrocytomas operated upon between 2000 and 2020. Next-generation DNA/RNA sequencing (NGS) and methylome analysis were performed to determine molecular alterations. Histology and NGS allowed the distinction of 5 tumor subgroups: glioblastoma IDH wildtype (GBM); diffuse midline glioma H3 K27M mutated (DMG-H3); high-grade astrocytoma with piloid features (HAP); diffuse astrocytoma IDH mutated (DA), diffuse leptomeningeal glioneural tumors (DGLN) and pilocytic astrocytoma (PA). Within all tumor entities GBM (median OS: 5.5 months), DMG-H3 (median OS: 13 months) and HAP (median OS: 8 months) showed a fatal prognosis. DMG-H3 tend to emerge in adolescence whereas GBM and HAP develop in the elderly. HAP are characterized by CDKN2A/B deletion and ATRX mutation. 50% of PA tumors carried a mutation in the PIK3CA gene which is seemingly associated with better outcome (median OS: PIK3CA mutated 107.5 vs 45.5 months in wildtype PA). This exploratory molecular profiling of spinal cord astrocytomas allows to identify distinct subgroups by combining molecular markers and histomorphology. DMG-H3 tend to develop in adolescence with a similar dismal prognosis like GBM and HAP in the elderly. We here describe spinal HAP with a distinct molecular profile for the first time.
    Keywords:  Molecular profile; Next-generation sequencing; Prognostic factor; Spinal astrocytoma
    DOI:  https://doi.org/10.1186/s40478-021-01222-6
  9. Nat Commun. 2021 Jun 29. 12(1): 4031
    Resolution of tissue signatures of therapy response in patients with recurrent GBM treated with neoadjuvant anti-PD1.
    Yue Lu, Alphonsus H C Ng, Frances E Chow, Richard G Everson, Beth A Helmink, Michael T Tetzlaff, Rohit Thakur, Jennifer A Wargo, Timothy F Cloughesy, Robert M Prins, James R Heath.
      The response of patients with recurrent glioblastoma multiforme to neoadjuvant immune checkpoint blockade has been challenging to interpret due to the inter-patient and intra-tumor heterogeneity. We report on a comparative analysis of tumor tissues collected from patients with recurrent glioblastoma and high-risk melanoma, both treated with neoadjuvant checkpoint blockade. We develop a framework that uses multiplex spatial protein profiling, machine learning-based image analysis, and data-driven computational models to investigate the pathophysiological and molecular factors within the tumor microenvironment that influence treatment response. Using melanoma to guide the interpretation of glioblastoma analyses, we interrogate the protein expression in microscopic compartments of tumors, and determine the correlates of cytotoxic CD8+ T cells, tumor growth, treatment response, and immune cell-cell interaction. This work reveals similarities shared between glioblastoma and melanoma, immunosuppressive factors that are unique to the glioblastoma microenvironment, and potential co-targets for enhancing the efficacy of neoadjuvant immune checkpoint blockade.
    DOI:  https://doi.org/10.1038/s41467-021-24293-4
  10. Cancers (Basel). 2021 Jun 26. pii: 3198. [Epub ahead of print]13(13):
    High-Resolution Cartography of the Transcriptome and Methylome Landscapes of Diffuse Gliomas.
    Edith Willscher, Lydia Hopp, Markus Kreuz, Maria Schmidt, Siras Hakobyan, Arsen Arakelyan, Bettina Hentschel, David T W Jones, Stefan M Pfister, Markus Loeffler, Henry Loeffler-Wirth, Hans Binder.
      Molecular mechanisms of lower-grade (II-III) diffuse gliomas (LGG) are still poorly understood, mainly because of their heterogeneity. They split into astrocytoma- (IDH-A) and oligodendroglioma-like (IDH-O) tumors both carrying mutations(s) at the isocitrate dehydrogenase (IDH) gene and into IDH wild type (IDH-wt) gliomas of glioblastoma resemblance. We generated detailed maps of the transcriptomes and DNA methylomes, revealing that cell functions divided into three major archetypic hallmarks: (i) increased proliferation in IDH-wt and, to a lesser degree, IDH-O; (ii) increased inflammation in IDH-A and IDH-wt; and (iii) the loss of synaptic transmission in all subtypes. Immunogenic properties of IDH-A are diverse, partly resembling signatures observed in grade IV mesenchymal glioblastomas or in grade I pilocytic astrocytomas. We analyzed details of coregulation between gene expression and DNA methylation and of the immunogenic micro-environment presumably driving tumor development and treatment resistance. Our transcriptome and methylome maps support personalized, case-by-case views to decipher the heterogeneity of glioma states in terms of data portraits. Thereby, molecular cartography provides a graphical coordinate system that links gene-level information with glioma subtypes, their phenotypes, and clinical context.
    Keywords:  DNA methylation; gene expression; grade II–IV gliomas; integrative bioinformatics; molecular subtypes; self-organizing maps machine learning; tumor evolution; tumor heterogeneity
    DOI:  https://doi.org/10.3390/cancers13133198
  11. Lancet Oncol. 2021 Jun 29. pii: S1470-2045(21)00245-X. [Epub ahead of print]
    Neural stem cell delivery of an oncolytic adenovirus in newly diagnosed malignant glioma: a first-in-human, phase 1, dose-escalation trial.
    Jawad Fares, Atique U Ahmed, Ilya V Ulasov, Adam M Sonabend, Jason Miska, Catalina Lee-Chang, Irina V Balyasnikova, James P Chandler, Jana Portnow, Matthew C Tate, Priya Kumthekar, Rimas V Lukas, Sean A Grimm, Ann K Adams, Charles D Hébert, Theresa V Strong, Christina Amidei, Victor A Arrieta, Markella Zannikou, Craig Horbinski, Hui Zhang, Kirsten Bell Burdett, David T Curiel, Sean Sachdev, Karen S Aboody, Roger Stupp, Maciej S Lesniak.
       BACKGROUND: Malignant glioma is the most common and lethal primary brain tumour, with dismal survival rates and no effective treatment. We examined the safety and activity of NSC-CRAd-S-pk7, an engineered oncolytic adenovirus delivered by neural stem cells (NSCs), in patients with newly diagnosed high-grade glioma.
    METHODS: This was a first-in-human, open-label, phase 1, dose-escalation trial done to determine the maximal tolerated dose of NSC-CRAd-S-pk7, following a 3 + 3 design. Patients with newly diagnosed, histologically confirmed, high-grade gliomas (WHO grade III or IV) were recruited. After neurosurgical resection, NSC-CRAd-S-pk7 was injected into the walls of the resection cavity. The first patient cohort received a dose starting at 6·25 × 1010 viral particles administered by 5·00 × 107 NSCs, the second cohort a dose of 1·25 × 1011 viral particles administered by 1·00 × 108 NSCs, and the third cohort a dose of 1·875 × 1011 viral particles administered by 1·50 × 108 NSCs. No further dose escalation was planned. Within 10-14 days, treatment with temozolomide and radiotherapy was initiated. Primary endpoints were safety and toxicity profile and the maximum tolerated dose for a future phase 2 trial. All analyses were done in all patients who were included in the trial and received the study treatment and were not excluded from the study. Recruitment is complete and the trial is finished. The trial is registered with ClinicalTrials.gov, NCT03072134.
    FINDINGS: Between April 24, 2017, and Nov 13, 2019, 12 patients with newly diagnosed, malignant gliomas were recruited and included in the safety analysis. Histopathological evaluation identified 11 (92%) of 12 patients with glioblastoma and one (8%) of 12 patients with anaplastic astrocytoma. The median follow-up was 18 months (IQR 14-22). One patient receiving 1·50 × 108 NSCs loading 1·875 × 1011 viral particles developed viral meningitis (grade 3) due to the inadvertent injection of NSC-CRAd-S-pk7 into the lateral ventricle. Otherwise, treatment was safe as no formal dose-limiting toxicity was reached, so 1·50 × 108 NSCs loading 1·875 × 1011 viral particles was recommended as a phase 2 trial dose. There were no treatment-related deaths. The median progression-free survival was 9·1 months (95% CI 8·5-not reached) and median overall survival was 18·4 months (15·7-not reached).
    INTERPRETATION: NSC-CRAd-S-pk7 treatment was feasible and safe. Our immunological and histopathological findings support continued investigation of NSC-CRAd-S-pk7 in a phase 2/3 clinical trial.
    FUNDING: US National Institutes of Health.
    DOI:  https://doi.org/10.1016/S1470-2045(21)00245-X
  12. Neuro Oncol. 2021 Jul 02. pii: noab154. [Epub ahead of print]
    BOLD Asynchrony Elucidates Tumor Burden in IDH-Mutated Gliomas.
    Petros D Petridis, Craig Horenstein, Brianna Pereira, Peter Wu, Jorge Samanamud, Tamara Marie, Deborah Boyett, Tejaswi Sudhakar, Sameer A Sheth, Guy M McKhann, Michael B Sisti, Jeffrey N Bruce, Peter Canoll, Jack Grinband.
       BACKGROUND: Gliomas comprise the most common type of primary brain tumor, are highly invasive, and often fatal. IDH-mutated gliomas are particularly challenging to image and there is currently no clinically accepted method for identifying the extent of tumor burden in these neoplasms. This uncertainty poses a challenge to clinicians who must balance the need to treat the tumor while sparing healthy brain from iatrogenic damage. The purpose of this study was to investigate the feasibility of using resting-state blood oxygen level dependent (BOLD) functional magnetic resonance imaging (fMRI) to detect glioma-related asynchrony in vascular dynamics for distinguishing tumor from healthy brain.
    METHODS: Twenty-four stereotactically localized biopsies were obtained during open surgical resection from ten treatment-naïve patients with IDH-mutated gliomas who received standard of care preoperative imaging as well as echo-planar resting-state BOLD fMRI. Signal intensity for BOLD asynchrony and standard of care imaging was compared to cell counts of total cellularity (H&E), tumor density (IDH1 & Sox2), cellular proliferation (Ki67), and neuronal density (NeuN), for each corresponding sample.
    RESULTS: BOLD asynchrony was directly related to total cellularity (H&E, p = 4 x 10 -5), tumor density (IDH1, p = 4 x 10 -5; Sox2, p = 3 x 10 -5), cellular proliferation (Ki67, p = 0.002), and as well as inversely related to neuronal density (NeuN, p = 1 x 10 -4).
    CONCLUSIONS: Asynchrony in vascular dynamics, as measured by resting-state BOLD fMRI, correlates with tumor burden and provides a radiographic delineation of tumor boundaries in IDH-mutated gliomas.
    Keywords:  BOLD asynchrony; IDH-mutated glioma; infiltration; resting-state fMRI; tumor burden
    DOI:  https://doi.org/10.1093/neuonc/noab154
  13. Cancers (Basel). 2021 Jun 02. pii: 2756. [Epub ahead of print]13(11):
    Association of Circadian Clock Gene Expression with Glioma Tumor Microenvironment and Patient Survival.
    Julianie De La Cruz Minyety, Dorela D Shuboni-Mulligan, Nicole Briceno, Demarrius Young, Mark R Gilbert, Orieta Celiku, Terri S Armstrong.
      Circadian clock genes have been linked to clinical outcomes in cancer, including gliomas. However, these studies have not accounted for established markers that predict the prognosis, including mutations in Isocitrate Dehydrogenase (IDH), which characterize the majority of lower-grade gliomas and secondary high-grade gliomas. To demonstrate the connection between circadian clock genes and glioma outcomes while accounting for the IDH mutational status, we analyzed multiple publicly available gene expression datasets. The unsupervised clustering of 13 clock gene transcriptomic signatures from The Cancer Genome Atlas showed distinct molecular subtypes representing different disease states and showed the differential prognosis of these groups by a Kaplan-Meier analysis. Further analyses of these groups showed that a low period (PER) gene expression was associated with the negative prognosis and enrichment of the immune signaling pathways. These findings prompted the exploration of the relationship between the microenvironment and clock genes in additional datasets. Circadian clock gene expression was found to be differentially expressed across the anatomical tumor location and cell type. Thus, the circadian clock expression is a potential predictive biomarker in glioma, and further mechanistic studies to elucidate the connections between the circadian clock and microenvironment are warranted.
    Keywords:  IDH mutational status; PER2; circadian clock genes; glioma; immune signature
    DOI:  https://doi.org/10.3390/cancers13112756
  14. Cancers (Basel). 2021 Jun 19. pii: 3055. [Epub ahead of print]13(12):
    Dual Role of Integrin Alpha-6 in Glioblastoma: Supporting Stemness in Proneural Stem-Like Cells While Inducing Radioresistance in Mesenchymal Stem-Like Cells.
    Elisabetta Stanzani, Leire Pedrosa, Guillaume Bourmeau, Oceane Anezo, Aleix Noguera-Castells, Anna Esteve-Codina, Lorena Passoni, Michela Matteoli, Núria de la Iglesia, Giorgio Seano, Fina Martínez-Soler, Avelina Tortosa.
      Therapeutic resistance after multimodal therapy is the most relevant cause of glioblastoma (GBM) recurrence. Extensive cellular heterogeneity, mainly driven by the presence of GBM stem-like cells (GSCs), strongly correlates with patients' prognosis and limited response to therapies. Defining the mechanisms that drive stemness and control responsiveness to therapy in a GSC-specific manner is therefore essential. Here we investigated the role of integrin a6 (ITGA6) in controlling stemness and resistance to radiotherapy in proneural and mesenchymal GSCs subtypes. Using cell sorting, gene silencing, RNA-Seq, and in vitro assays, we verified that ITGA6 expression seems crucial for proliferation and stemness of proneural GSCs, while it appears not to be relevant in mesenchymal GSCs under basal conditions. However, when challenged with a fractionated protocol of radiation therapy, comparable to that used in the clinical setting, mesenchymal GSCs were dependent on integrin a6 for survival. Specifically, GSCs with reduced levels of ITGA6 displayed a clear reduction of DNA damage response and perturbation of cell cycle pathways. These data indicate that ITGA6 inhibition is able to overcome the radioresistance of mesenchymal GSCs, while it reduces proliferation and stemness in proneural GSCs. Therefore, integrin a6 controls crucial characteristics across GBM subtypes in GBM heterogeneous biology and thus may represent a promising target to improve patient outcomes.
    Keywords:  ITGA6; cancer stem cells; glioblastoma; integrin alpha-6; mesenchymal subtype; radioresistance; radiotherapy
    DOI:  https://doi.org/10.3390/cancers13123055
  15. Viruses. 2021 Jun 17. pii: 1158. [Epub ahead of print]13(6):
    The Current Landscape of Oncolytic Herpes Simplex Viruses as Novel Therapies for Brain Malignancies.
    Joshua D Bernstock, Samantha E Hoffman, Jason A Chen, Saksham Gupta, Ari D Kappel, Timothy R Smith, E Antonio Chiocca.
      Despite advances in surgical resection and chemoradiation, high-grade brain tumors continue to be associated with significant morbidity/mortality. Novel therapeutic strategies and approaches are, therefore, desperately needed for patients and their families. Given the success experienced in treating multiple other forms of cancer, immunotherapy and, in particular, immunovirotherapy are at the forefront amongst novel therapeutic strategies that are currently under investigation for incurable brain tumors. Accordingly, herein, we provide a focused mini review of pertinent oncolytic herpes viruses (oHSV) that are being investigated in clinical trials.
    Keywords:  brain tumors; glioblastoma (GBM); herpes simplex virus (HSV); immunotherapy; immunovirotherapy; oncolytic virus
    DOI:  https://doi.org/10.3390/v13061158
  16. Mol Cell. 2021 Jul 01. pii: S1097-2765(21)00492-5. [Epub ahead of print]81(13): 2686-2687
    A delicate initiation: Lipolysis of lipid droplets fuels glioblastoma.
    Kailin Yang, Jeremy N Rich.
      Liu et al. (2021) demonstrate that CHKα2 is capable of promoting lipolysis of lipid droplets through mechanisms that require sequential steps of post-translational modifications after glucose deprivation. Intriguingly, the oxidation of fatty acids derived from lipid droplets is essential for the survival of tumor cells that informs clinical outcome among glioblastoma patients.
    DOI:  https://doi.org/10.1016/j.molcel.2021.06.013
  17. Mol Oncol. 2021 Jul 02.
    PRRX1 induced by BMP signaling decreases tumorigenesis by epigenetically regulating glioma-initiating cell properties via DNA methyltransferase 3A.
    Ryo Tanabe, Kohei Miyazono, Tomoki Todo, Nobuhito Saito, Caname Iwata, Akiyoshi Komuro, Satoshi Sakai, Erna Raja, Daizo Koinuma, Masato Morikawa, Bengt Westermark, Carl-Henrik Heldin.
      Glioma-initiating cells (GICs), a major source of glioblastoma recurrence, are characterized by the expression of neural stem cell markers and the ability to grow by forming non-adherent spheres under serum-free conditions. Bone morphogenetic proteins (BMPs), members of the transforming growth factor-β family, induce differentiation of GICs and suppress their tumorigenicity. However, the mechanisms underlying the BMP-induced loss of GIC stemness have not been fully elucidated. Here, we show that paired related homeobox 1 (PRRX1) induced by BMPs decreases the CD133-positive GIC population and inhibits tumorigenic activity of GICs in vivo. Of the two splice isoforms of PRRX1, the longer isoform, pmx-1b, but not the shorter isoform, pmx-1a, induces GIC differentiation. Upon BMP stimulation, pmx-1b interacts with the DNA methyltransferase DNMT3A and induces promoter methylation of the PROM1 gene encoding CD133. Silencing DNMT3A maintains PROM1 expression and increases the CD133-positive GIC population. Thus, pmx-1b promotes loss of stem-cell-like properties of GICs through region-specific epigenetic regulation of CD133 expression by recruiting DNMT3A, which is associated with decreased tumorigenicity of GICs.
    Keywords:  BMP; CD133; DNA methyltransferase; PRRX1; cancer-initiating cell; glioblastoma
    DOI:  https://doi.org/10.1002/1878-0261.13051
  18. Oncogene. 2021 Jun 29.
    Dual role of WNT5A in promoting endothelial differentiation of glioma stem cells and angiogenesis of glioma derived endothelial cells.
    Taoliang Chen, Fabing Zhang, Jie Liu, Zhilin Huang, Yaofeng Zheng, Shaokang Deng, Yang Liu, Jihui Wang, Xinlin Sun.
      Glioma is a devastating cancer with a rich vascular network. No anti-angiogenic treatment is available for prolonging the overall survival of glioma patients. Recent studies have demonstrated that the endothelial differentiation of glioma stem cells (GSCs) into glioma-derived endothelial cells (GDECs) may be a novel target for anti-angiogenic therapy in glioma; however, the underlying mechanisms of this process remain unknown. Here, we report that wingless-related integration site (WNT) family member 5A (WNT5A) plays significant roles in GSC endothelial differentiation and GDECs angiogenesis. WNT5A is preferentially secreted by GDECs, and inhibition of WNT5A suppresses angiogenesis and tumorigenesis in GDECs. Silencing of WNT5A in GDECs also disrupts the impact of GDECs on stimulating GSC endothelial differentiation. Frizzled-4 is a receptor that mediates the effect of WNT5A on GSC endothelial differentiation and angiogenesis of GDECs via GSK3β/β-catenin/epithelial-mesenchymal transition signalling. The shWNT5A@cRGD-DDD liposomes, targeting WNT5A, exert anti-angiogenic effects in vivo. In this study, we identified that WNT5A has a dual functional role in modulating the endothelial differentiation of GSCs and angiogenesis of GDECs, indicating that WNT5A is a potential target for anti-angiogenesis-based therapeutics in glioma.
    DOI:  https://doi.org/10.1038/s41388-021-01922-2
  19. Nat Commun. 2021 Jul 02. 12(1): 4089
    Patient-derived models recapitulate heterogeneity of molecular signatures and drug response in pediatric high-grade glioma.
    Chen He, Ke Xu, Xiaoyan Zhu, Paige S Dunphy, Brian Gudenas, Wenwei Lin, Nathaniel Twarog, Laura D Hover, Chang-Hyuk Kwon, Lawryn H Kasper, Junyuan Zhang, Xiaoyu Li, James Dalton, Barbara Jonchere, Kimberly S Mercer, Duane G Currier, William Caufield, Yingzhe Wang, Jia Xie, Alberto Broniscer, Cynthia Wetmore, Santhosh A Upadhyaya, Ibrahim Qaddoumi, Paul Klimo, Frederick Boop, Amar Gajjar, Jinghui Zhang, Brent A Orr, Giles W Robinson, Michelle Monje, Burgess B Freeman Iii, Martine F Roussel, Paul A Northcott, Taosheng Chen, Zoran Rankovic, Gang Wu, Jason Chiang, Christopher L Tinkle, Anang A Shelat, Suzanne J Baker.
      Pediatric high-grade glioma (pHGG) is a major contributor to cancer-related death in children. In vitro and in vivo disease models reflecting the intimate connection between developmental context and pathogenesis of pHGG are essential to advance understanding and identify therapeutic vulnerabilities. Here we report establishment of 21 patient-derived pHGG orthotopic xenograft (PDOX) models and eight matched cell lines from diverse groups of pHGG. These models recapitulate histopathology, DNA methylation signatures, mutations and gene expression patterns of the patient tumors from which they were derived, and include rare subgroups not well-represented by existing models. We deploy 16 new and existing cell lines for high-throughput screening (HTS). In vitro HTS results predict variable in vivo response to PI3K/mTOR and MEK pathway inhibitors. These unique new models and an online interactive data portal for exploration of associated detailed molecular characterization and HTS chemical sensitivity data provide a rich resource for pediatric brain tumor research.
    DOI:  https://doi.org/10.1038/s41467-021-24168-8
  20. Neuro Oncol. 2021 Jun 29. pii: noab106. [Epub ahead of print]
    The 2021 WHO Classification of Tumors of the Central Nervous System: a summary.
    David N Louis, Arie Perry, Pieter Wesseling, Daniel J Brat, Ian A Cree, Dominique Figarella-Branger, Cynthia Hawkins, H K Ng, Stefan M Pfister, Guido Reifenberger, Riccardo Soffietti, Andreas von Deimling, David W Ellison.
      The fifth edition of the WHO Classification of Tumors of the Central Nervous System (CNS), published in 2021, is the sixth version of the international standard for the classification of brain and spinal cord tumors. Building on the 2016 updated fourth edition and the work of the Consortium to Inform Molecular and Practical Approaches to CNS Tumor Taxonomy, the 2021 fifth edition introduces major changes that advance the role of molecular diagnostics in CNS tumor classification. At the same time, it remains wedded to other established approaches to tumor diagnosis such as histology and immunohistochemistry. In doing so, the fifth edition establishes some different approaches to both CNS tumor nomenclature and grading and it emphasizes the importance of integrated diagnoses and layered reports. New tumor types and subtypes are introduced, some based on novel diagnostic technologies such as DNA methylome profiling. The present review summarizes the major general changes in the 2021 fifth edition classification and the specific changes in each taxonomic category. It is hoped that this summary provides an overview to facilitate more in-depth exploration of the entire fifth edition of the WHO Classification of Tumors of the Central Nervous System.
    Keywords:  World Health Organization; brain tumor; central nervous system; classification; diagnosis
    DOI:  https://doi.org/10.1093/neuonc/noab106
  21. Lancet Oncol. 2021 Jun 29. pii: S1470-2045(21)00296-5. [Epub ahead of print]
    Hitchhiking to brain tumours: stem cell delivery of oncolytic viruses.
    Juan Fueyo, Candelaria Gomez-Manzano, Frederick F Lang, Marta M Alonso.
      
    DOI:  https://doi.org/10.1016/S1470-2045(21)00296-5
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