bims-malgli Biomed News
on Biology of malignant gliomas
Issue of 2020–12–20
twenty papers selected by
Oltea Sampetrean, Keio University
  1. Tumor cell network integration in glioma represents a stemness feature.
  2. Co-expression of cancer driver genes: IDH-wildtype glioblastoma-derived tumorspheres.
  3. Characterization and oncolytic virus targeting of FAP-expressing tumor-associated pericytes in glioblastoma.
  4. Combined PI3Kα-mTOR Targeting of Glioma Stem Cells.
  5. Targeting the Ubiquitin System in Glioblastoma.
  6. To Become or Not to Become Tumorigenic: Subventricular Zone Versus Hippocampal Neural Stem Cells.
  7. Multifaceted WNT Signaling at the Crossroads Between Epithelial-Mesenchymal Transition and Autophagy in Glioblastoma.
  8. Cell surface antigen profiling of pediatric brain tumors: B7-H3 is consistently expressed and can be targeted via local or systemic CAR T-cell delivery.
  9. Inhibition of 2-Hydroxyglutarate Elicits Metabolic-reprograming and Mutant IDH1 Glioma Immunity in Mice.
  10. Modulation of the chemokine/chemokine receptor axis as a novel approach for glioma therapy.
  11. The nuclear DICER-circular RNA complex drives the deregulation of the glioblastoma cell microRNAome.
  12. Update on Chemotherapeutic Approaches and Management of Bevacizumab Usage for Glioblastoma.
  13. Glioblastoma epigenome profiling identifies SOX10 as a master regulator of molecular tumour subtype.
  14. AN1-type zinc finger protein 3 (ZFAND3) is a transcriptional regulator that drives Glioblastoma invasion.
  15. A Glioma Subtype Arises from Immature Cells and Depends on PDGFRA.
  16. CRISPR Screening of CAR T Cells and Cancer Stem Cells Reveals Critical Dependencies for Cell-Based Therapies.
  17. Deeper and Deeper on the Role of BK and Kir4.1 Channels in Glioblastoma Invasiveness: A Novel Summative Mechanism?
  18. The Molecular and Microenvironmental Landscape of Glioblastomas: Implications for the Novel Treatment Choices.
  19. Tumor cell and immune cell profiles in primary human glioblastoma: Impact on patient outcome.
  20. A New Landscape for Systemic Pharmacotherapy of Recurrent Glioblastoma?
  1. Neuro Oncol. 2020 Dec 15. pii: noaa275. [Epub ahead of print]
    Tumor cell network integration in glioma represents a stemness feature.
    Ruifan Xie, Tobias Kessler, Julia Grosch, Ling Hai, Varun Venkataramani, Lulu Huang, Dirk C Hoffmann, Gergely Solecki, Miriam Ratliff, Matthias Schlesner, Wolfgang Wick, Frank Winkler.
       BACKGROUND: Malignant gliomas including glioblastomas are characterized by a striking cellular heterogeneity, which includes a subpopulation of glioma cells that becomes highly resistant by integration into tumor microtube (TM)-connected multicellular networks.
    METHODS: A novel functional approach to detect, isolate and characterize glioma cell subpopulations with respect to in vivo network integration is established, combining a dye staining method with intravital two-photon microscopy, FACS sorting, molecular profiling, and gene reporter studies.
    RESULTS: Glioblastoma cells that are part of the TM-connected tumor network show activated neurodevelopmental and glioma progression gene expression pathways. Importantly, many of them revealed profiles indicative of increased cellular stemness, including high expression of nestin. TM-connected glioblastoma cells also had a higher potential for re-initiation of brain tumor growth. Long-term tracking of tumor cell nestin expression in vivo revealed a stronger TM network integration and higher radioresistance of the nestin-high subpopulation. Glioblastoma cells that were both nestin-high and network-integrated were particularly able to adapt to radiotherapy with increased TM formation.
    CONCLUSION: Multiple stem-like features are strongly enriched in a fraction of network-integrated glioma cells, explaining their particular resilience.
    Keywords:  Glioblastoma; cancer stem cells; glioma; networks; tumor microtubes
    DOI:  https://doi.org/10.1093/neuonc/noaa275
  2. J Transl Med. 2020 Dec 14. 18(1): 482
    Co-expression of cancer driver genes: IDH-wildtype glioblastoma-derived tumorspheres.
    Seon-Jin Yoon, Hye Young Son, Jin-Kyoung Shim, Ju Hyung Moon, Eui-Hyun Kim, Jong Hee Chang, Wan Yee Teo, Se Hoon Kim, Sahng Wook Park, Yong-Min Huh, Seok-Gu Kang.
       BACKGROUND: Driver genes of GBM may be crucial for the onset of isocitrate dehydrogenase (IDH)-wildtype (WT) glioblastoma (GBM). However, it is still unknown whether the genes are expressed in the identical cluster of cells. Here, we have examined the gene expression patterns of GBM tissues and patient-derived tumorspheres (TSs) and aimed to find a progression-related gene.
    METHODS: We retrospectively collected primary IDH-WT GBM tissue samples (n = 58) and tumor-free cortical tissue samples (control, n = 20). TSs are isolated from the IDH-WT GBM tissue with B27 neurobasal medium. Associations among the driver genes were explored in the bulk tissue, bulk cell, and a single cell RNAsequencing techniques (scRNAseq) considering the alteration status of TP53, PTEN, EGFR, and TERT promoter as well as MGMT promoter methylation. Transcriptomic perturbation by temozolomide (TMZ) was examined in the two TSs.
    RESULTS: We comprehensively compared the gene expression of the known driver genes as well as MGMT, PTPRZ1, or IDH1. Bulk RNAseq databases of the primary GBM tissue revealed a significant association between TERT and TP53 (p < 0.001, R = 0.28) and its association increased in the recurrent tumor (p  < 0.001, R = 0.86). TSs reflected the tissue-level patterns of association between the two genes (p < 0.01, R = 0.59, n = 20). A scRNAseq data of a TS revealed the TERT and TP53 expressing cells are in a same single cell cluster. The driver-enriched cluster dominantly expressed the glioma-associated long noncoding RNAs. Most of the driver-associated genes were downregulated after TMZ except IGFBP5.
    CONCLUSIONS: GBM tissue level expression patterns of EGFR, TERT, PTEN, IDH1, PTPRZ1, and MGMT are observed in the GBM TSs. The driver gene-associated cluster of the GBM single cells were enriched with the glioma-associated long noncoding RNAs.
    Keywords:  Isocitrate dehydrogenase-wildtype glioblastoma; Single cell RNAseq; Transcriptome; Tumorsphere
    DOI:  https://doi.org/10.1186/s12967-020-02647-8
  3. Acta Neuropathol Commun. 2020 Dec 11. 8(1): 221
    Characterization and oncolytic virus targeting of FAP-expressing tumor-associated pericytes in glioblastoma.
    Ming Li, Guoping Li, Juri Kiyokawa, Zain Tirmizi, Leland G Richardson, Jianfang Ning, Saumya Das, Robert L Martuza, Anat Stemmer-Rachamimov, Samuel D Rabkin, Hiroaki Wakimoto.
      Cancer-associated fibroblasts (CAFs) are activated fibroblasts constituting the major stromal components in many types of cancer. CAFs contribute to hallmarks of cancer such as proliferation, invasion and immunosuppressive tumor microenvironment, and are associated with poor prognosis of patients with cancer. However, in glioblastoma (GBM), the most common and aggressive primary malignant brain tumor, our knowledge about CAFs or CAF-like stromal cells is limited. Here, using commonly accepted CAF markers, we characterized CAF-like cell populations in clinical glioma specimens and datasets along with mouse models of GBM. We found that tumor-associated pericytes marked by co-expression of fibroblast activation protein α (FAP) and PDGFRβ represent major stromal cell subsets in both human GBM and mouse GBM models, while a fraction of mesenchymal neoplastic cells also express FAP in patient tumors. Since oncolytic viruses can kill cancer cells and simultaneously modulate the tumor microenvironment by impacting non-neoplastic populations such as immune cells and tumor vasculature, we further investigated the ability of oncolytic viruses to target GBM-associated stromal cells. An oncolytic adenovirus, ICOVIR15, carrying ∆24-E1A and an RGD-fiber, infects and depletes FAP+ pericytes as well as GBM cells in murine GBM. Our study thus identifies FAP+/PDGFRβ+ pericytes as a major CAF-like stromal cell population in GBM, and highlights the unique property of this oncolytic adenovirus to target both GBM cells and GBM-associated stromal FAP+ cells.
    Keywords:  FAP; Glioblastoma; Oncolytic virus; Pericytes; Tumor-associated fibroblasts
    DOI:  https://doi.org/10.1186/s40478-020-01096-0
  4. Sci Rep. 2020 Dec 14. 10(1): 21873
    Combined PI3Kα-mTOR Targeting of Glioma Stem Cells.
    Frank D Eckerdt, Jonathan B Bell, Christopher Gonzalez, Michael S Oh, Ricardo E Perez, Candice Mazewski, Mariafausta Fischietti, Stewart Goldman, Ichiro Nakano, Leonidas C Platanias.
      Glioblastoma (GBM) is the most common and lethal primary intrinsic tumour of the adult brain and evidence indicates disease progression is driven by glioma stem cells (GSCs). Extensive advances in the molecular characterization of GBM allowed classification into proneural, mesenchymal and classical subtypes, and have raised expectations these insights may predict response to targeted therapies. We utilized GBM neurospheres that display GSC characteristics and found activation of the PI3K/AKT pathway in sphere-forming cells. The PI3Kα selective inhibitor alpelisib blocked PI3K/AKT activation and inhibited spheroid growth, suggesting an essential role for the PI3Kα catalytic isoform. p110α expression was highest in the proneural subtype and this was associated with increased phosphorylation of AKT. Further, employing the GBM BioDP, we found co-expression of PIK3CA with the neuronal stem/progenitor marker NES was associated with poor prognosis in PN GBM patients, indicating a unique role for PI3Kα in PN GSCs. Alpelisib inhibited GSC neurosphere growth and these effects were more pronounced in GSCs of the PN subtype. The antineoplastic effects of alpelisib were substantially enhanced when combined with pharmacologic mTOR inhibition. These findings identify the alpha catalytic PI3K isoform as a unique therapeutic target in proneural GBM and suggest that pharmacological mTOR inhibition may sensitize GSCs to selective PI3Kα inhibition.
    DOI:  https://doi.org/10.1038/s41598-020-78788-z
  5. Front Oncol. 2020 ;10 574011
    Targeting the Ubiquitin System in Glioblastoma.
    Nico Scholz, Kathreena M Kurian, Florian A Siebzehnrubl, Julien D F Licchesi.
      Glioblastoma is the most common primary brain tumor in adults with poor overall outcome and 5-year survival of less than 5%. Treatment has not changed much in the last decade or so, with surgical resection and radio/chemotherapy being the main options. Glioblastoma is highly heterogeneous and frequently becomes treatment-resistant due to the ability of glioblastoma cells to adopt stem cell states facilitating tumor recurrence. Therefore, there is an urgent need for novel therapeutic strategies. The ubiquitin system, in particular E3 ubiquitin ligases and deubiquitinating enzymes, have emerged as a promising source of novel drug targets. In addition to conventional small molecule drug discovery approaches aimed at modulating enzyme activity, several new and exciting strategies are also being explored. Among these, PROteolysis TArgeting Chimeras (PROTACs) aim to harness the endogenous protein turnover machinery to direct therapeutically relevant targets, including previously considered "undruggable" ones, for proteasomal degradation. PROTAC and other strategies targeting the ubiquitin proteasome system offer new therapeutic avenues which will expand the drug development toolboxes for glioblastoma. This review will provide a comprehensive overview of E3 ubiquitin ligases and deubiquitinating enzymes in the context of glioblastoma and their involvement in core signaling pathways including EGFR, TGF-β, p53 and stemness-related pathways. Finally, we offer new insights into how these ubiquitin-dependent mechanisms could be exploited therapeutically for glioblastoma.
    Keywords:  E3 ubiquitin ligases; PROTAC (proteolysis-targeting chimeric molecule); cancer; deubiquinating enzymes; glioblastoma; stem cell; ubiquitin; ubiquitin-proteasome system
    DOI:  https://doi.org/10.3389/fonc.2020.574011
  6. Front Oncol. 2020 ;10 602217
    To Become or Not to Become Tumorigenic: Subventricular Zone Versus Hippocampal Neural Stem Cells.
    Ángela Fontán-Lozano, Sara Morcuende, Mª América Davis-López de Carrizosa, Beatriz Benítez-Temiño, Rebeca Mejías, Esperanza R Matarredona.
      Neural stem cells (NSCs) persist in the adult mammalian brain in two neurogenic regions: the subventricular zone lining the lateral ventricles and the dentate gyrus of the hippocampus. Compelling evidence suggests that NSCs of the subventricular zone could be the cell type of origin of glioblastoma, the most devastating brain tumor. Studies in glioblastoma patients revealed that NSCs of the tumor-free subventricular zone, harbor cancer-driver mutations that were found in the tumor cells but were not present in normal cortical tissue. Endogenous mutagenesis can also take place in hippocampal NSCs. However, to date, no conclusive studies have linked hippocampal mutations with glioblastoma development. In addition, glioblastoma cells often invade or are closely located to the subventricular zone, whereas they do not tend to infiltrate into the hippocampus. In this review we will analyze possible causes by which subventricular zone NSCs might be more susceptible to malignant transformation than their hippocampal counterparts. Cellular and molecular differences between the two neurogenic niches, as well as genotypic and phenotypic characteristics of their respective NSCs will be discussed regarding why the cell type originating glioblastoma brain tumors has been linked mainly to subventricular zone, but not to hippocampal NSCs.
    Keywords:  cancer-driver mutations; glioblastoma; neural stem cells; neurogenesis; oncogenicity
    DOI:  https://doi.org/10.3389/fonc.2020.602217
  7. Front Oncol. 2020 ;10 597743
    Multifaceted WNT Signaling at the Crossroads Between Epithelial-Mesenchymal Transition and Autophagy in Glioblastoma.
    Bárbara Paranhos Coelho, Camila Felix de Lima Fernandes, Jacqueline Marcia Boccacino, Maria Clara da Silva Souza, Maria Isabel Melo-Escobar, Rodrigo Nunes Alves, Mariana Brandão Prado, Rebeca Piatniczka Iglesia, Giovanni Cangiano, Giulia La Rocca Mazzaro, Marilene Hohmuth Lopes.
      Tumor cells can employ epithelial-mesenchymal transition (EMT) or autophagy in reaction to microenvironmental stress. Importantly, EMT and autophagy negatively regulate each other, are able to interconvert, and both have been shown to contribute to drug-resistance in glioblastoma (GBM). EMT has been considered one of the mechanisms that confer invasive properties to GBM cells. Autophagy, on the other hand, may show dual roles as either a GBM-promoter or GBM-suppressor, depending on microenvironmental cues. The Wingless (WNT) signaling pathway regulates a plethora of developmental and biological processes such as cellular proliferation, adhesion and motility. As such, GBM demonstrates deregulation of WNT signaling in favor of tumor initiation, proliferation and invasion. In EMT, WNT signaling promotes induction and stabilization of different EMT activators. WNT activity also represses autophagy, while nutrient deprivation induces β-catenin degradation via autophagic machinery. Due to the importance of the WNT pathway to GBM, and the role of WNT signaling in EMT and autophagy, in this review we highlight the effects of the WNT signaling in the regulation of both processes in GBM, and discuss how the crosstalk between EMT and autophagy may ultimately affect tumor biology.
    Keywords:  WNT signaling; autophagy; chaperone-mediated autophagy; epithelial-mesenchymal transition; glioblastoma; metabolic reprograming; microautophagy
    DOI:  https://doi.org/10.3389/fonc.2020.597743
  8. Neuro Oncol. 2020 Dec 15. pii: noaa278. [Epub ahead of print]
    Cell surface antigen profiling of pediatric brain tumors: B7-H3 is consistently expressed and can be targeted via local or systemic CAR T-cell delivery.
    Dalia Haydar, Haley Houke, Jason Chiang, Zhongzhen Yi, Zelda Odé, Kenneth Caldwell, Xiaoyan Zhu, Kimberly S Mercer, Jennifer L Stripay, Timothy I Shaw, Peter Vogel, Christopher DeRenzo, Suzanne J Baker, Martine F Roussel, Stephen Gottschalk, Giedre Krenciute.
       BACKGROUND: Immunotherapy with CAR T-cells is actively being explored for pediatric brain tumors in preclinical models and early phase clinical studies. At present it is unclear which CAR target antigens are consistently expressed across different pediatric brain tumor types. In addition, the extent of HLA class-I expression is unknown, which is critical for tumor recognition by conventional αβTCR T-cells.
    METHODS: We profiled 49 low- and high-grade pediatric brain tumor patient-derived orthotopic xenografts (PDOX) by flow analysis for the expression of five CAR targets (B7-H3, GD2, IL13Rα2, EphA2, HER2), and HLA class-I. In addition, we generated B7-H3-CAR T-cells and evaluated their antitumor activity in vitro and in vivo.
    RESULTS: We established an expression hierarchy for the analyzed antigens (B7-H3 = GD2 >> IL13Rα2 > HER2 = EphA2) and demonstrated that antigen expression is heterogenous. All high-grade gliomas expressed HLA class-I, but only 57.1% of other tumor subtypes had detectable expression. We then selected B7-H3 as a target for CAR T-cell therapy. B7-H3-CAR T-cells recognized tumor cells in an antigen-dependent fashion. Local or systemic administration of B7-H3-CAR T-cells induced tumor regression in PDOX and immunocompetent murine glioma models resulting in a significant survival advantage.
    CONCLUSIONS: Our study highlights the importance of studying target antigen and HLA class-I expression in PDOX samples for the future design of immunotherapies. In addition, our results support active preclinical and clinical exploration of B7-H3-targeted CAR T-cell therapies for a broad spectrum of pediatric brain tumors.
    Keywords:  B7-H3; CAR T-cell immunotherapy; GD2; HLA; immunocompetent and PDOX models; pediatric brain tumor
    DOI:  https://doi.org/10.1093/neuonc/noaa278
  9. J Clin Invest. 2020 Dec 17. pii: 139542. [Epub ahead of print]
    Inhibition of 2-Hydroxyglutarate Elicits Metabolic-reprograming and Mutant IDH1 Glioma Immunity in Mice.
    Padma Kadiyala, Stephen V Carney, Jessica C Gauss, Maria B Garcia-Fabiani, Santiago Haase, Mahmoud S Alghamri, Felipe J Núñez, Yayuan Liu, Minzhi Yu, Ayman W Taher, Fernando M Nunez, Dan Li, Marta B Edwards, Celina G Kleer, Henry Appelman, Yilun Sun, Lili Zhao, James J Moon, Anna Schwendeman, Pedro R Lowenstein, Maria G Castro.
      Mutant isocitrate-dehydrogenase-1 (IDH1-R132H; mIDH1) is a hallmark of adult gliomas. Lower grade mIDH1 gliomas are classified into two molecular subgroups: (i) 1p/19q co-deletion/TERT-promoter mutations or (ii) inactivating mutations in α-thalassemia/mental retardation syndrome X-linked (ATRX) and TP53. This work, focuses on gliomas' subtype harboring mIDH1, TP53 and ATRX inactivation. IDH1-R132H is a gain-of-function mutation that converts α-ketoglutarate into 2-hydroxyglutarate (D-2HG). The role of D-2HG within the tumor microenvironment of mIDH1/mATRX/mTP53 gliomas remains unexplored. Inhibition of D-2HG, when used as monotherapy or in combination with radiation and temozolomide (IR/TMZ), led to increased median survival (MS) of mIDH1 glioma bearing mice. Also, D-2HG inhibition elicited anti-mIDH1 glioma immunological memory. In response to D-2HG inhibition, PD-L1 expression levels on mIDH1-glioma cells increased to similar levels as observed in wild-type-IDH1 gliomas. Thus, we combined D-2HG inhibition/IR/TMZ with anti-PDL1 immune checkpoint-blockade and observed complete tumor regression in 60% of mIDH1 glioma bearing mice. This combination strategy reduced T-cell exhaustion and favored the generation of memory CD8+ T-cells. Our findings demonstrate that metabolic reprogramming elicits anti-mIDH1 glioma immunity, leading to increased MS and immunological memory. Our preclinical data supports the testing of IDH-R132H inhibitors in combination with IR/TMZ and anti-PDL1 as targeted therapy for mIDH1/mATRX/mTP53 glioma patients.
    Keywords:  Adaptive immunity; Brain cancer; Immunology; Immunotherapy; Neuroscience
    DOI:  https://doi.org/10.1172/JCI139542
  10. Pharmacol Ther. 2020 Dec 11. pii: S0163-7258(20)30321-1. [Epub ahead of print] 107790
    Modulation of the chemokine/chemokine receptor axis as a novel approach for glioma therapy.
    Gregory P Takacs, Joseph A Flores-Toro, Jeffrey K Harrison.
      Chemokines are a large subfamily of cytokines known for their ability to facilitate cell migration, most notably leukocytes, throughout the body. Chemokines are necessary for a functioning immune system in both health and disease and have received considerable attention for their roles in orchestrating temporal-spatial regulation of immune cell populations in cancer. Gliomas comprise a group of common central nervous system (CNS) primary tumors that are extremely challenging to treat. Immunotherapy approaches for highly malignant brain tumors offer an exciting new avenue for therapeutic intervention but so far, have seen limited successful clinical outcomes. Herein we focus on important chemokine/chemokine receptor systems in the regulation of pro- and anti-tumor mechanisms, highlighting potential therapeutic advantages of modulating these systems in malignant gliomas and other cancers.
    Keywords:  Chemokine; Glioblastoma; Immunotherapy; MDSC; Microglia; Tumor microenvironment
    DOI:  https://doi.org/10.1016/j.pharmthera.2020.107790
  11. Sci Adv. 2020 Dec;pii: eabc0221. [Epub ahead of print]6(51):
    The nuclear DICER-circular RNA complex drives the deregulation of the glioblastoma cell microRNAome.
    A Bronisz, A K Rooj, K Krawczyński, P Peruzzi, E Salińska, I Nakano, B Purow, E A Chiocca, J Godlewski.
      The assortment of cellular microRNAs ("microRNAome") is a vital readout of cellular homeostasis, but the mechanisms that regulate the microRNAome are poorly understood. The microRNAome of glioblastoma is substantially down-regulated in comparison to the normal brain. Here, we find malfunction of the posttranscriptional maturation of the glioblastoma microRNAome and link it to aberrant nuclear localization of DICER, the major enzymatic complex responsible for microRNA maturation. Analysis of DICER's nuclear interactome reveals the presence of an RNA binding protein, RBM3, and of a circular RNA, circ2082, within the complex. Targeting of this complex by knockdown of circ2082 results in the restoration of cytosolic localization of DICER and widespread derepression of the microRNAome, leading to transcriptome-wide rearrangements that mitigate the tumorigenicity of glioblastoma cells in vitro and in vivo with correlation to favorable outcomes in patients with glioblastoma. These findings uncover the mechanistic foundation of microRNAome deregulation in malignant cells.
    DOI:  https://doi.org/10.1126/sciadv.abc0221
  12. Pharmaceuticals (Basel). 2020 Dec 16. pii: E470. [Epub ahead of print]13(12):
    Update on Chemotherapeutic Approaches and Management of Bevacizumab Usage for Glioblastoma.
    Yusuke Funakoshi, Nobuhiro Hata, Daisuke Kuga, Ryusuke Hatae, Yuhei Sangatsuda, Yutaka Fujioka, Kosuke Takigawa, Masahiro Mizoguchi.
      Glioblastoma, the most common primary brain tumor in adults, has one of the most dismal prognoses in cancer. In 2009, bevacizumab was approved for recurrent glioblastoma in the USA. To evaluate the clinical impact of bevacizumab as a first-line drug for glioblastoma, two randomized clinical trials, AVAglio and RTOG 0825, were performed. Bevacizumab was found to improve progression-free survival (PFS) and was reported to be beneficial for maintaining patient performance status as an initial treatment. These outcomes led to bevacizumab approval in Japan in 2013 as an insurance-covered first-line drug for glioblastoma concurrently with its second-line application. However, prolongation of overall survival was not evinced in these clinical trials; hence, the clinical benefit of bevacizumab for newly diagnosed glioblastomas remains controversial. A recent meta-analysis of randomized controlled trials of bevacizumab combined with temozolomide in recurrent glioblastoma also showed an effect only on PFS, and the benefit of bevacizumab even for recurrent glioblastoma is controversial. Here, we discuss the clinical impact of bevacizumab for glioblastoma treatment by reviewing previous clinical trials and real-world evidence by focusing on Japanese experiences. Moreover, the efficacy and safety of bevacizumab are summarized, and we provide suggestions for updating the approaches and management of bevacizumab.
    Keywords:  bevacizumab; chemotherapy; glioblastoma; survival; vascular endothelial growth factor (VEGF)
    DOI:  https://doi.org/10.3390/ph13120470
  13. Nat Commun. 2020 Dec 18. 11(1): 6434
    Glioblastoma epigenome profiling identifies SOX10 as a master regulator of molecular tumour subtype.
    Yonghe Wu, Michael Fletcher, Zuguang Gu, Qi Wang, Barbara Costa, Anna Bertoni, Ka-Hou Man, Magdalena Schlotter, Jörg Felsberg, Jasmin Mangei, Martje Barbus, Ann-Christin Gaupel, Wei Wang, Tobias Weiss, Roland Eils, Michael Weller, Haikun Liu, Guido Reifenberger, Andrey Korshunov, Peter Angel, Peter Lichter, Carl Herrmann, Bernhard Radlwimmer.
      Glioblastoma frequently exhibits therapy-associated subtype transitions to mesenchymal phenotypes with adverse prognosis. Here, we perform multi-omic profiling of 60 glioblastoma primary tumours and use orthogonal analysis of chromatin and RNA-derived gene regulatory networks to identify 38 subtype master regulators, whose cell population-specific activities we further map in published single-cell RNA sequencing data. These analyses identify the oligodendrocyte precursor marker and chromatin modifier SOX10 as a master regulator in RTK I-subtype tumours. In vitro functional studies demonstrate that SOX10 loss causes a subtype switch analogous to the proneural-mesenchymal transition observed in patients at the transcriptomic, epigenetic and phenotypic levels. SOX10 repression in an in vivo syngeneic graft glioblastoma mouse model results in increased tumour invasion, immune cell infiltration and significantly reduced survival, reminiscent of progressive human glioblastoma. These results identify SOX10 as a bona fide master regulator of the RTK I subtype, with both tumour cell-intrinsic and microenvironmental effects.
    DOI:  https://doi.org/10.1038/s41467-020-20225-w
  14. Nat Commun. 2020 12 11. 11(1): 6366
    AN1-type zinc finger protein 3 (ZFAND3) is a transcriptional regulator that drives Glioblastoma invasion.
    Anne Schuster, Eliane Klein, Virginie Neirinckx, Arnon Møldrup Knudsen, Carina Fabian, Ann-Christin Hau, Monika Dieterle, Anais Oudin, Petr V Nazarov, Anna Golebiewska, Arnaud Muller, Daniel Perez-Hernandez, Sophie Rodius, Gunnar Dittmar, Rolf Bjerkvig, Christel Herold-Mende, Barbara Klink, Bjarne Winther Kristensen, Simone P Niclou.
      The infiltrative nature of Glioblastoma (GBM), the most aggressive primary brain tumor, critically prevents complete surgical resection and masks tumor cells behind the blood brain barrier reducing the efficacy of systemic treatment. Here, we use a genome-wide interference screen to determine invasion-essential genes and identify the AN1/A20 zinc finger domain containing protein 3 (ZFAND3) as a crucial driver of GBM invasion. Using patient-derived cellular models, we show that loss of ZFAND3 hampers the invasive capacity of GBM, whereas ZFAND3 overexpression increases motility in cells that were initially not invasive. At the mechanistic level, we find that ZFAND3 activity requires nuclear localization and integral zinc-finger domains. Our findings indicate that ZFAND3 acts within a nuclear protein complex to activate gene transcription and regulates the promoter of invasion-related genes such as COL6A2, FN1, and NRCAM. Further investigation in ZFAND3 function in GBM and other invasive cancers is warranted.
    DOI:  https://doi.org/10.1038/s41467-020-20029-y
  15. Cancer Discov. 2020 Dec 11.
    A Glioma Subtype Arises from Immature Cells and Depends on PDGFRA.
      H3.3G34R/V-mutant high-grade gliomas became reliant on activating PDGFRA mutations for maintenance.
    DOI:  https://doi.org/10.1158/2159-8290.CD-RW2020-180
  16. Cancer Discov. 2020 Dec 16. pii: CD-20-1243. [Epub ahead of print]
    CRISPR Screening of CAR T Cells and Cancer Stem Cells Reveals Critical Dependencies for Cell-Based Therapies.
    Dongrui Wang, Briana C Prager, Ryan C Gimple, Brenda Aguilar, Darya Alizadeh, Hongzhen Tang, Deguan Lv, Renate Starr, Alfonso Brito, Qiulian Wu, Leo J Y Kim, Zhixin Qiu, Peng Lin, Michael H Lorenzini, Behnam Badie, Stephen J Forman, Qi Xie, Christine E Brown, Jeremy N Rich.
      Glioblastoma (GBM) contains self-renewing GBM stem cells (GSCs) potentially amenable to immunologic targeting, but chimeric antigen receptor (CAR) T cell therapy has demonstrated limited clinical responses in GBM. Here, we interrogated molecular determinants of CAR-mediated GBM killing through whole-genome CRISPR screens in both CAR T cells and patient-derived GSCs. Screening of CAR T cells identified dependencies for effector functions, including TLE4 and IKZF2. Targeted knockout of these genes enhanced CAR antitumor efficacy. Bulk and single cell-RNA sequencing of edited CAR T cells revealed transcriptional profiles of superior effector function and inhibited exhaustion responses. Reciprocal screening of GSCs identified genes essential for susceptibility to CAR-mediated killing, including RELA and NPLOC4, the knockout of which altered tumor-immune signaling and increased responsiveness of CAR therapy. Overall, CRISPR screening of CAR T cells and GSCs discovered avenues for enhancing CAR therapeutic efficacy against GBM, with the potential to be extended to other solid tumors.
    DOI:  https://doi.org/10.1158/2159-8290.CD-20-1243
  17. Front Neurosci. 2020 ;14 595664
    Deeper and Deeper on the Role of BK and Kir4.1 Channels in Glioblastoma Invasiveness: A Novel Summative Mechanism?
    Federico Brandalise, Daniela Ratto, Roberta Leone, Federico Olivero, Elisa Roda, Carlo Alessandro Locatelli, Maria Grazia Bottone, Paola Rossi.
      In the last decades, increasing evidence has revealed that a large number of channel protein and ion pumps exhibit impaired expression in cancers. This dysregulation is responsible for high proliferative rates as well as migration and invasiveness, reflected in the recently coined term oncochannelopathies. In glioblastoma (GBM), the most invasive and aggressive primary brain tumor, GBM cells modify their ionic equilibrium in order to change their volume as a necessary step prior to migration. This mechanism involves increased expression of BK channels and downregulation of the normally widespread Kir4.1 channels, as noted in GBM biopsies from patients. Despite a large body of work implicating BK channels in migration in response to an artificial intracellular calcium rise, little is known about how this channel acts in GBM cells at resting membrane potential (RMP), as compared to other channels that are constitutively open, such as Kir4.1. In this review we propose that a residual fraction of functionally active Kir4.1 channels mediates a small, but continuous, efflux of potassium at the more depolarized RMP of GBM cells. In addition, coinciding with transient membrane deformation and the intracellular rise in calcium concentration, brief activity of BK channels can induce massive and rapid cytosolic water loss that reduces cell volume (cell shrinkage), a necessary step for migration within the brain parenchyma.
    Keywords:  BK channel; Kir4.1; cancer; channelopathy; glioblastoma
    DOI:  https://doi.org/10.3389/fnins.2020.595664
  18. Front Neurosci. 2020 ;14 603647
    The Molecular and Microenvironmental Landscape of Glioblastomas: Implications for the Novel Treatment Choices.
    Federica Di Cintio, Michele Dal Bo, Lorena Baboci, Elena De Mattia, Maurizio Polano, Giuseppe Toffoli.
      Glioblastoma (GBM) is the most frequent and aggressive primary central nervous system tumor. Surgery followed by radiotherapy and chemotherapy with alkylating agents constitutes standard first-line treatment of GBM. Complete resection of the GBM tumors is generally not possible given its high invasive features. Although this combination therapy can prolong survival, the prognosis is still poor due to several factors including chemoresistance. In recent years, a comprehensive characterization of the GBM-associated molecular signature has been performed. This has allowed the possibility to introduce a more personalized therapeutic approach for GBM, in which novel targeted therapies, including those employing tyrosine kinase inhibitors (TKIs), could be employed. The GBM tumor microenvironment (TME) exerts a key role in GBM tumor progression, in particular by providing an immunosuppressive state with low numbers of tumor-infiltrating lymphocytes (TILs) and other immune effector cell types that contributes to tumor proliferation and growth. The use of immune checkpoint inhibitors (ICIs) has been successfully introduced in numerous advanced cancers as well as promising results have been shown for the use of these antibodies in untreated brain metastases from melanoma and from non-small cell lung carcinoma (NSCLC). Consequently, the use of PD-1/PD-L1 inhibitors has also been proposed in several clinical trials for the treatment of GBM. In the present review, we will outline the main GBM molecular and TME aspects providing also the grounds for novel targeted therapies and immunotherapies using ICIs for GBM.
    Keywords:  CAR-T; GBM; immune checkpoint inhibitors; treatment resistance; tumor microenvironment; tyrosine kinase inhibitors
    DOI:  https://doi.org/10.3389/fnins.2020.603647
  19. Brain Pathol. 2020 Dec 14. e12927
    Tumor cell and immune cell profiles in primary human glioblastoma: Impact on patient outcome.
    María González-Tablas, Álvaro Otero, Daniel Arandia, Daniel Pascual, Laura Ruiz, Pablo Sousa, Andoni García, Juan Carlos Roa, Jorge Javier Md Villaseñor, Luis Torres, Maria do Rosário Almeida, Javier Pedro Ortiz, Adelaida Nieto, Alberto Orfao, María Dolores Tabernero.
       BACKGROUND: The distribution and role of tumor infiltrating leucocytes in glioblastoma (GBM) remain largely unknown. Here, we investigated the cellular composition of 55 primary (adult) GBM samples by flowcytometry and correlated the tumor immune profile with patient features at diagnosis and outcome.
    METHODS: GBM single-cell suspensions were stained at diagnosis (n=44) and recurrence following radiotherapy and chemotherapy (n=11) with a panel of 8-color monoclonal antibody combinations for identification and enumeration of (GFAP+ CD45- ) tumor and normal astrocytic cells, infiltrating myeloid cells - i.e. microglial and blood-derived tumor-associated macrophages (TAM), M1-like and M2-like TAM, neutrophils and myeloid-derived suppressor cells (MDSC) - and tumor-infiltrating lymphocytes (TIL) - i.e. CD3+ T-cells and their TCD4+ , TCD8+ , TCD4- CD8- and (CD25+ CD127lo ) regulatory (T-regs) subsets, (CD19+ CD20+ ) B-cells and (CD16+ ) NK-cells - .
    RESULTS: Overall, GBM samples consisted of a major population (mean±1SD) of tumor and normal astrocytic cells (73%±16%) together with a significant but variable fraction of immune cells (24%±18%). Within myeloid cells, TAM predominated (13%±12%) including both microglial cells (10%±11%) and blood-derived macrophages (3%±5%), in addition to a smaller proportion of neutrophils (5%±9%) and MDSC (4%±8%). Lymphocytes were less represented and mostly included TCD4+ (0.5%±0.7%) and TCD8+ cells (0.6%±0.7%), together with lower numbers of TCD4- CD8- T-cells (0.2%±0.4%), T-regs (0.1%±0.2%), B-lymphocytes (0.1%±0.2%) and NK-cells (0.05%±0.05%). Overall, three distinct immune profiles were identified: cases with a minor fraction of leucocytes, tumors with predominance of TAM and neutrophils, and cases with mixed infiltration by TAM, neutrophils and T-lymphocytes. Untreated GBM patients with mixed myeloid and lymphoid immune infiltrates showed a significantly shorter patient overall survival vs the other two groups, in the absence of gains of the EGFR gene (p=0.02).
    CONCLUSIONS: Here we show that immune cell infiltrates are systematically present in GBM, with highly variable levels and immune profiles. Patients with mixed myeloid and T-lymphoid infiltrates showed worse outcome.
    Keywords:  Glioblastoma; immune cells; lymphocytes; microenvironment; microglia; myeloid cells
    DOI:  https://doi.org/10.1111/bpa.12927
  20. Cancers (Basel). 2020 Dec 15. pii: E3775. [Epub ahead of print]12(12):
    A New Landscape for Systemic Pharmacotherapy of Recurrent Glioblastoma?
    Giuseppe Lombardi, Ahmed Idbaih, Emilie Le Rhun, Matthias Preusser, Vittorina Zagonel, Pim French.
      Glioblastoma is the most common and aggressive primary malignant brain tumor in adult patients [...].
    DOI:  https://doi.org/10.3390/cancers12123775
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