bims-malgli Biomed News
on Biology of malignant gliomas
Issue of 2022‒11‒06
ten papers selected by
Oltea Sampetrean
Keio University
  1. cGAS-STING pathway targeted therapies and their applications in the treatment of high-grade glioma.
  2. Glioblastoma stem cell HISTArionics.
  3. Factors affecting the radiation response in glioblastoma.
  4. Turning on the light for brain tumor surgery: A 5-aminolevulinic acid story.
  5. ARL13B promotes angiogenesis and glioma growth by activating VEGFA-VEGFR2 signaling.
  6. Neuronal CaMKK2 promotes immunosuppression and checkpoint blockade resistance in glioblastoma.
  7. Advances in 3D culture systems for therapeutic discovery and development in brain cancer.
  8. Extracellular vesicles-transferred SBSN drives glioma aggressiveness by activating NF-κB via ANXA1-dependent ubiquitination of NEMO.
  9. Spatial analysis of the glioblastoma proteome reveals specific molecular signatures and markers of survival.
  10. TERT promotor status does not add prognostic information in IDH-wildtype glioblastomas fulfilling other diagnostic WHO criteria: A report of the RANO resect group.
  1. F1000Res. 2022 ;11 1010
    cGAS-STING pathway targeted therapies and their applications in the treatment of high-grade glioma.
    Shashwat Tripathi, Hinda Najem, Akanksha Sanjay Mahajan, Peng Zhang, Justin T Low, Alexander H Stegh, Michael A Curran, David M Ashley, Charles David James, Amy B Heimberger.
      Median survival of patients with glioblastoma (GBM) treated with standard of care which consists of maximal safe resection of the contrast-enhancing portion of the tumor followed by radiation therapy with concomitant adjuvant temozolomide (TMZ) remains 15 months. The tumor microenvironment (TME) is known to contain immune suppressive myeloid cells with minimal effector T cell infiltration. Stimulator of interferon genes (STING) is an important activator of immune response and results in production of Type 1 interferon and antigen presentation by myeloid cells. This review will discuss important developments in STING agonists, potential biomarkers for STING response, and new combinatorial therapeutic approaches in gliomas.
    Keywords:  STING Agonist; T cells; cGAS-STING; glioblastoma; immune cells; immune therapies; myeloid cells; tumor microenvironment
    DOI:  https://doi.org/10.12688/f1000research.125163.1
  2. Cell Stem Cell. 2022 Nov 03. pii: S1934-5909(22)00422-2. [Epub ahead of print]29(11): 1509-1510
    Glioblastoma stem cell HISTArionics.
    Siva Kumar Natarajan, Sriram Venneti.
      Glioblastomas are lethal malignancies that possess a rapidly evolving microenvironment containing necrotic/hypoxic areas, aberrant microvasculature, and glioblastoma stem cells (GSCs) that promote tumor growth, recurrence, and treatment resistance. Chen et al. find that GSCs drive integrated epigenetic and metabolic control of angiogenesis via histamine and propose antihistamines as potential therapies.
    DOI:  https://doi.org/10.1016/j.stem.2022.10.004
  3. Neurooncol Adv. 2022 Jan-Dec;4(1):4(1): vdac156
    Factors affecting the radiation response in glioblastoma.
    Radhika Aiyappa-Maudsley, Anthony J Chalmers, Jason L Parsons.
      Glioblastoma (GBM) is a highly invasive primary brain tumor in adults with a 5-year survival rate of less than 10%. Conventional radiotherapy with photons, along with concurrent and adjuvant temozolomide, is the mainstay for treatment of GBM although no significant improvement in survival rates has been observed over the last 20 years. Inherent factors such as tumor hypoxia, radioresistant GBM stem cells, and upregulated DNA damage response mechanisms are well established as contributing to treatment resistance and tumor recurrence. While it is understandable that efforts have focused on targeting these factors to overcome this phenotype, there have also been striking advances in precision radiotherapy techniques, including proton beam therapy and carbon ion radiotherapy (CIRT). These enable higher doses of radiation to be delivered precisely to the tumor, while minimizing doses to surrounding normal tissues and organs at risk. These alternative radiotherapy techniques also benefit from increased biological effectiveness, particularly in the case of CIRT. Although not researched extensively to date, combining these new radiation modalities with radio-enhancing agents may be particularly effective in improving outcomes for patients with GBM.
    Keywords:  Carbon ions; DNA damage repair; glioblastoma; ionizing radiation; proton beam therapy
    DOI:  https://doi.org/10.1093/noajnl/vdac156
  4. Neuro Oncol. 2022 Nov 02. 24(Supplement_6): S52-S61
    Turning on the light for brain tumor surgery: A 5-aminolevulinic acid story.
    David J McCracken, Alexander J Schupper, Nikita Lakomkin, James Malcolm, David Painton Bray, Constantinos G Hadjipanayis.
      To aid surgeons in more complete and safe resection of brain tumors, adjuvant technologies have been developed to improve visualization of target tissue. Fluorescence-guided surgery relies on the use of fluorophores and specific light wavelengths to better delineate tumor tissue, inflammation, and areas of blood-brain barrier breakdown. 5-aminolevulinic acid (5-ALA), the first fluorophore developed specifically for brain tumors, accumulates within tumor cells, improving visualization of tumors both at the core, and infiltrative margin. Here, we describe the background of how 5-ALA integrated into the modern neurosurgery practice, clinical evidence for the current use of 5-ALA, and future directions for its role in neurosurgical oncology. Maximal safe resection remains the standard of care for most brain tumors. Gross total resection of high-grade gliomas (HGGs) is associated with greater overall survival and progression-free survival (PFS) in comparison to subtotal resection or adjuvant treatment therapies alone.1-3 A major challenge neurosurgeons encounter when resecting infiltrative gliomas is identification of the glioma tumor margin to perform a radical resection while avoiding and preserving eloquent regions of the brain. 5-aminolevulinic acid (5-ALA) remains the only optical-imaging agent approved by the FDA for use in glioma surgery and identification of tumor tissue.4 A multicenter randomized, controlled trial revealed that 5-ALA fluorescence-guided surgery (FGS) almost doubled the extent of tumor resection and also improved 6-month PFS.5 In this review, we will highlight the current evidence for use of 5-ALA FGS in brain tumor surgery, as well as discuss the future directions for its use.
    Keywords:  5-aminolevulinic acid, 5-ALA; extent of resection; fluorescence-guided surgery; glioma; metastasis
    DOI:  https://doi.org/10.1093/neuonc/noac191
  5. Neuro Oncol. 2022 Nov 02. pii: noac245. [Epub ahead of print]
    ARL13B promotes angiogenesis and glioma growth by activating VEGFA-VEGFR2 signaling.
    Limin Chen, Xinsheng Xie, Tiantian Wang, Linlin Xu, Zhenyu Zhai, Haibin Wu, Libin Deng, Quqin Lu, Zhengjun Chen, Xiao Yang, Hua Lu, Ye-Guang Chen, Shiwen Luo.
      BACKGROUND: Tumor angiogenesis is essential for solid tumor progression, invasion and metastasis. The aim of this study was to identify potential signaling pathways involved in tumor angiogenesis.METHODS: Genetically engineered mouse models were used to investigate the effects of endothelial ARL13B(ADP-ribosylation factor-like GTPase 13B) overexpression and deficiency on retinal and cerebral vasculature. An intracranially transplanted glioma model and a subcutaneously implanted melanoma model were employed to examine the effects of ARL13B on tumor growth and angiogenesis. Immunohistochemistry was used to measure ARL13B in glioma tissues, and scRNA-seq was used to analyze glioma and endothelial ARL13B expression. GST-fusion protein-protein interaction and coimmunoprecipitation assays were used to determine the ARL13B-VEGFR2 interaction. Immunobloting, qPCR, dual-luciferase reporter assay and functional experiments were performed to evaluate the effects of ARL13B on VEGFR2 activation.
    RESULTS: Endothelial ARL13B regulates vascular development of both the retina and brain in mice. Also, ARL13B in endothelial cells regulated the growth of intracranially transplanted glioma cells and subcutaneously implanted melanoma cells by controlling tumor angiogenesis. Interestingly, this effect was attributed to ARL13B interaction with VEGFR2, through which ARL13B regulated the membrane and ciliary localization of VEGFR2 and consequently activated its downstream signaling in endothelial cells. Consistent with its oncogenic role, ARL13B was highly expressed in human gliomas, which was well correlated with the poor prognosis of glioma patients. Remarkably, ARL13B, transcriptionally regulated by ZEB1, enhanced the expression of VEGFA by activating Hedgehog signaling in glioma cells.
    CONCLUSIONS: ARL13B promotes angiogenesis and tumor growth by activating VEGFA-VEGFR2 signaling. Thus, targeting ARL13B might serve as a potential approach for developing an anti-glioma or anti-melanoma therapy.
    Keywords:  ARL13B; VEGFR2; intercellular communication; tumor angiogenesis; vascular development
    DOI:  https://doi.org/10.1093/neuonc/noac245
  6. Nat Commun. 2022 Oct 29. 13(1): 6483
    Neuronal CaMKK2 promotes immunosuppression and checkpoint blockade resistance in glioblastoma.
    William H Tomaszewski, Jessica Waibl-Polania, Molly Chakraborty, Jonathan Perera, Jeremy Ratiu, Alexandra Miggelbrink, Donald P McDonnell, Mustafa Khasraw, David M Ashley, Peter E Fecci, Luigi Racioppi, Luis Sanchez-Perez, Michael D Gunn, John H Sampson.
      Glioblastoma (GBM) is notorious for its immunosuppressive tumor microenvironment (TME) and is refractory to immune checkpoint blockade (ICB). Here, we identify calmodulin-dependent kinase kinase 2 (CaMKK2) as a driver of ICB resistance. CaMKK2 is highly expressed in pro-tumor cells and is associated with worsened survival in patients with GBM. Host CaMKK2, specifically, reduces survival and promotes ICB resistance. Multimodal profiling of the TME reveals that CaMKK2 is associated with several ICB resistance-associated immune phenotypes. CaMKK2 promotes exhaustion in CD8+ T cells and reduces the expansion of effector CD4+ T cells, additionally limiting their tumor penetrance. CaMKK2 also maintains myeloid cells in a disease-associated microglia-like phenotype. Lastly, neuronal CaMKK2 is required for maintaining the ICB resistance-associated myeloid phenotype, is deleterious to survival, and promotes ICB resistance. Our findings reveal CaMKK2 as a contributor to ICB resistance and identify neurons as a driver of immunotherapeutic resistance in GBM.
    DOI:  https://doi.org/10.1038/s41467-022-34175-y
  7. Drug Discov Today. 2022 Nov 01. pii: S1359-6446(22)00419-6. [Epub ahead of print] 103426
    Advances in 3D culture systems for therapeutic discovery and development in brain cancer.
    Janith Wanigasekara, Patrick J Cullen, Paula Bourke, Brijesh Tiwari, James F Curtin.
      This review focuses on recent advances in 3D culture systems that promise more accurate therapeutic models of the glioblastoma multiforme (GBM) tumor microenvironment (TME), such as the unique anatomical, cellular, and molecular features evident in human GBM. The key components of a GBM TME are outlined, including microbiomes, vasculature, extracellular matrix (ECM), infiltrating parenchymal and peripheral immune cells and molecules, and chemical gradients. 3D culture systems are evaluated against 2D culture systems and in vivo animal models. The main 3D culture techniques available are compared, with an emphasis on identifying key gaps in knowledge for the development of suitable platforms to accurately model the intricate components of the GBM TME.
    Keywords:  3D bioprinter; 3D cell culture; glioma; hydrogels; scaffolds; tumor microenvironment
    DOI:  https://doi.org/10.1016/j.drudis.2022.103426
  8. Oncogene. 2022 Oct 31.
    Extracellular vesicles-transferred SBSN drives glioma aggressiveness by activating NF-κB via ANXA1-dependent ubiquitination of NEMO.
    Han Chen, Xuhong Chen, Zhuojun Zhang, Wenhao Bao, Zhiqing Gao, Difeng Li, Xiaoyi Xie, Ping Zhou, Chunxiao Yang, Zhongqiu Zhou, Jinyuan Pan, Xiangqin Kuang, Ruiming Tang, Zhengfu Feng, Lihuan Zhou, Dachun Zhu, Jianan Yang, Lan Wang, Hongbiao Huang, Daolin Tang, Jinbao Liu, Lili Jiang.
      Glioma is the most common malignant primary brain tumor with aggressiveness and poor prognosis. Although extracellular vesicles (EVs)-based cell-to-cell communication mediates glioma progression, the key molecular mediators of this process are still not fully understood. Herein, we elucidated an EVs-mediated transfer of suprabasin (SBSN), leading to the aggressiveness and progression of glioma. High levels of SBSN were positively correlated with clinical grade, predicting poor clinical prognosis of patients. Upregulation of SBSN promoted, while silencing of SBSN suppressed tumorigenesis and aggressiveness of glioma cells in vivo. EVs-mediated transfer of SBSN resulted in an increase in SBSN levels, which promoted the aggressiveness of glioma cells by enhancing migration, invasion, and angiogenesis of recipient glioma cells. Mechanistically, SBSN activated NF-κB signaling by interacting with annexin A1, which further induced Lys63-linked and Met1-linear polyubiquitination of NF-κB essential modulator (NEMO). In conclusion, the communication of SBSN-containing EVs within glioma cells drives the formation and development of tumors by activating NF-κB pathway, which may provide potential therapeutic target for clinical intervention in glioma.
    DOI:  https://doi.org/10.1038/s41388-022-02520-6
  9. Nat Commun. 2022 Nov 04. 13(1): 6665
    Spatial analysis of the glioblastoma proteome reveals specific molecular signatures and markers of survival.
    Marie Duhamel, Lauranne Drelich, Maxence Wisztorski, Soulaimane Aboulouard, Jean-Pascal Gimeno, Nina Ogrinc, Patrick Devos, Tristan Cardon, Michael Weller, Fabienne Escande, Fahed Zairi, Claude-Alain Maurage, Émilie Le Rhun, Isabelle Fournier, Michel Salzet.
      Molecular heterogeneity is a key feature of glioblastoma that impedes patient stratification and leads to large discrepancies in mean patient survival. Here, we analyze a cohort of 96 glioblastoma patients with survival ranging from a few months to over 4 years. 46 tumors are analyzed by mass spectrometry-based spatially-resolved proteomics guided by mass spectrometry imaging. Integration of protein expression and clinical information highlights three molecular groups associated with immune, neurogenesis, and tumorigenesis signatures with high intra-tumoral heterogeneity. Furthermore, a set of proteins originating from reference and alternative ORFs is found to be statistically significant based on patient survival times. Among these proteins, a 5-protein signature is associated with survival. The expression of these 5 proteins is validated by immunofluorescence on an additional cohort of 50 patients. Overall, our work characterizes distinct molecular regions within glioblastoma tissues based on protein expression, which may help guide glioblastoma prognosis and improve current glioblastoma classification.
    DOI:  https://doi.org/10.1038/s41467-022-34208-6
  10. Neurooncol Adv. 2022 Jan-Dec;4(1):4(1): vdac158
    TERT promotor status does not add prognostic information in IDH-wildtype glioblastomas fulfilling other diagnostic WHO criteria: A report of the RANO resect group.
    Philipp Karschnia, Jacob S Young, Antonio Dono, Levin Häni, Stephanie T Juenger, Tommaso Sciortino, Francesco Bruno, Nico Teske, Ramin A Morshed, Alexander F Haddad, Yalan Zhang, Sophia Stoecklein, Michael A Vogelbaum, Juergen Beck, Nitin Tandon, Shawn Hervey-Jumper, Annette M Molinaro, Roberta Rudà, Lorenzo Bello, Oliver Schnell, Yoshua Esquenazi, Maximilian I Ruge, Stefan J Grau, Martin van den Bent, Michael Weller, Mitchel S Berger, Susan M Chang, Joerg-Christian Tonn.
      
    DOI:  https://doi.org/10.1093/noajnl/vdac158
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