bims-malgli Biomed News
on Biology of malignant gliomas
Issue of 2023–06–04
ten papers selected by
Oltea Sampetrean, Keio University
  1. A Molecular Blueprint to Targeting ALK Gene Fusions in Glioblastoma.
  2. DNX-2401 plus Pembrolizumab Is Safe in Recurrent Glioblastoma.
  3. Dissecting Intra-tumor Heterogeneity in the Glioblastoma Microenvironment Using Fluorescence-Guided Multiple Sampling.
  4. Promising results for antisense RNA therapy in mouse models of diffuse midline glioma.
  5. TMIGD2 as a potential therapeutic target in glioma patients.
  6. The DRD2 antagonist haloperidol mediates autophagy-induced ferroptosis to increase temozolomide sensitivity by promoting endoplasmic reticulum stress in glioblastoma.
  7. macroH2A2 antagonizes epigenetic programs of stemness in glioblastoma.
  8. Elevated FOXG1 in glioblastoma stem cells cooperates with Wnt/β-catenin to induce exit from quiescence.
  9. The SNP rs755622 is associated with immune activation in glioblastoma.
  10. Medulloblastoma and high-grade glioma organoids for drug screening, lineage tracing, co-culture and in vivo assay.
  1. Clin Cancer Res. 2023 Jun 01. OF1-OF3
    A Molecular Blueprint to Targeting ALK Gene Fusions in Glioblastoma.
    Stephen C Mack, Kelsey C Bertrand.
      Glioblastoma (GBM) is a heterogeneous brain tumor entity from infancy through adulthood. ALK gene fusions enriched in congenital and infant GBM have emerged as druggable driver alterations. Understanding the molecular basis and prevalence of ALK gene rearrangements will help define patients with GBM who may benefit from ALK-targeted therapy. See related article by Blandin et al., p. xxx.
    DOI:  https://doi.org/10.1158/1078-0432.CCR-23-0472
  2. Cancer Discov. 2023 Jun 02. OF1
    DNX-2401 plus Pembrolizumab Is Safe in Recurrent Glioblastoma.
      Pembrolizumab plus the oncolytic virus DNX-2401 is safe and efficacious in a subset of patients with glioblastoma.
    DOI:  https://doi.org/10.1158/2159-8290.CD-RW2023-083
  3. Mol Cancer Res. 2023 May 31. OF1-OF13
    Dissecting Intra-tumor Heterogeneity in the Glioblastoma Microenvironment Using Fluorescence-Guided Multiple Sampling.
    Leopoldo A García-Montaño, Yamhilette Licón-Muñoz, Frank J Martinez, Yasine R Keddari, Michael K Ziemke, Muhammad O Chohan, Sara G M Piccirillo.
      The treatment of the most aggressive primary brain tumor in adults, glioblastoma (GBM), is challenging due to its heterogeneous nature, invasive potential, and poor response to chemo- and radiotherapy. As a result, GBM inevitably recurs and only a few patients survive 5 years post-diagnosis. GBM is characterized by extensive phenotypic and genetic heterogeneity, creating a diversified genetic landscape and a network of biological interactions between subclones, ultimately promoting tumor growth and therapeutic resistance. This includes spatial and temporal changes in the tumor microenvironment, which influence cellular and molecular programs in GBM and therapeutic responses. However, dissecting phenotypic and genetic heterogeneity at spatial and temporal levels is extremely challenging, and the dynamics of the GBM microenvironment cannot be captured by analysis of a single tumor sample. In this review, we discuss the current research on GBM heterogeneity, in particular, the utility and potential applications of fluorescence-guided multiple sampling to dissect phenotypic and genetic intra-tumor heterogeneity in the GBM microenvironment, identify tumor and non-tumor cell interactions and novel therapeutic targets in areas that are key for tumor growth and recurrence, and improve the molecular classification of GBM.
    DOI:  https://doi.org/10.1158/1541-7786.MCR-23-0048
  4. Nat Rev Neurol. 2023 May 30.
    Promising results for antisense RNA therapy in mouse models of diffuse midline glioma.
    Caroline Barranco.
      
    DOI:  https://doi.org/10.1038/s41582-023-00829-8
  5. Front Immunol. 2023 ;14 1173518
    TMIGD2 as a potential therapeutic target in glioma patients.
    Chaimae Boulhen, Saadia Ait Ssi, Hamza Benthami, Ibtissam Razzouki, Abdelhakim Lakhdar, Mehdi Karkouri, Abdallah Badou.
       Introduction: Among all types of central nervous system cancers, glioma remains the most frequent primary brain tumor in adults. Despite significant advances in immunomodulatory therapies, notably immune checkpoint inhibitors, their effectiveness remains constrained due to glioma resistance. The discovery of TMIGD2 (Transmembrane and Immunoglobulin Domain Containing 2) as an immuno-stimulatory receptor, constitutively expressed on naive T cells and most natural killer (NK) cells, has emerged as an attractive immunotherapy target in a variety of cancers. The expression profile of TMIGD2 and its significance in the overall survival of glioma patients remains unknown.
    Methods: In the present study, we first assessed TMIGD2 mRNA expression using the Cancer Genome Atlas (TCGA) glioma transcriptome dataset (667 patients), followed by validation with the Chinese Glioma Genome Atlas (CGGA) cohort (693 patients). Secondly, we examined TMIGD2 protein staining in a series of 25 paraffin-embedded blocks from Moroccan glioma patients. The statistical analysis was performed using GraphPad Prism 8 software.
    Results: TMIGD2 expression was found to be significantly higher in astrocytoma, IDH-1 mutations, low-grade, and young glioma patients. TMIGD2 was expressed on immune cells and, surprisingly, on tumor cells of glioma patients. Interestingly, our study demonstrated that TMIGD2 expression was negatively correlated with angiogenesis, hypoxia, G2/M checkpoint, and epithelial to mesenchymal transition signaling pathways. We also demonstrated that dendritic cells, monocytes, NK cells, gd T cells, and naive CD8 T cell infiltration correlates positively with TMIGD2 expression. On the other hand, Mantel-Cox analysis demonstrated that increased expression of TMIGD2 in human gliomas is associated with good overall survival. Cox multivariable analysis revealed that TMIGD2 is an independent predictor of a good prognosis in glioma patients.
    Discussion: Taken together, our results highlight the tight implication of TMIGD2 in glioma progression and show its promising therapeutic potential as a stimulatory target for immunotherapy.
    Keywords:  TMIGD2; costimulatory; glioma; immunotherapy; prognosis
    DOI:  https://doi.org/10.3389/fimmu.2023.1173518
  6. Clin Cancer Res. 2023 May 30. pii: CCR-22-3971. [Epub ahead of print]
    The DRD2 antagonist haloperidol mediates autophagy-induced ferroptosis to increase temozolomide sensitivity by promoting endoplasmic reticulum stress in glioblastoma.
    Linyong Shi, Hanning Chen, Kunxiang Chen, Chengzong Zhong, Chong Song, Yifeng Huang, Tong Wang, Lei Chen, Chiyang Li, Annie Huang, Hong Li, Yuntao Lu.
       PURPOSE: Temozolomide (TMZ) resistance remains a major obstacle in the treatment of glioblastoma (GBM). The combination of TMZ with another agent could offer an improved treatment option if it could overcome chemoresistance and prevent side effects. Here, we determined the critical drug that cause ferroptosis in GBM cells and elucidated the possible mechanism by which drug combination overcomes chemoresistance.
    EXPERIMENTAL DESIGN: Haloperidol/TMZ synergism was assessed in GBM cell lines with different DRD2 expression in vitro and in vivo. Inhibitors of ferroptosis, autophagy, endoplasmic reticulum stress and cAMP/PKA were used to validate the specific mechanisms by which haloperidol and TMZ induce ferroptosis in GBM cells.
    RESULTS: In the present work, we demonstrate that the dopamine D2 receptor (DRD2) level is increased by TMZ in a time-dependent manner and is inversely correlated with TMZ sensitivity in GBM. The DRD2 antagonist haloperidol (HP), a butylbenzene antipsychotic, markedly induces ferroptosis and effectively enhances TMZ efficacy in vivo and in vitro. Mechanistically, HP suppressed the effect of TMZ on cAMP by antagonizing DRD2 receptor activity, and the increases in cAMP/PKA triggered endoplasmic reticulum stress, which led to autophagy and ferroptosis. Furthermore, elevated autophagy mediates downregulation of FTH1 expression at the posttranslational level in an autophagy-dependent manner and ultimately leads to ferroptosis.
    CONCLUSIONS: Our results provide experimental evidence for repurposing HP as an effective adjunct therapy to inhibit adaptive TMZ resistance in order to enhance the efficacy of chemoradiotherapy in GBM, a strategy that may have broad prospects for clinical application.
    DOI:  https://doi.org/10.1158/1078-0432.CCR-22-3971
  7. Nat Commun. 2023 May 27. 14(1): 3062
    macroH2A2 antagonizes epigenetic programs of stemness in glioblastoma.
    Ana Nikolic, Francesca Maule, Anna Bobyn, Katrina Ellestad, Seungil Paik, Sajid A Marhon, Parinaz Mehdipour, Xueqing Lun, Huey-Miin Chen, Claire Mallard, Alexander J Hay, Michael J Johnston, Christopher J Gafuik, Franz J Zemp, Yaoqing Shen, Nicoletta Ninkovic, Katalin Osz, Elodie Labit, N Daniel Berger, Duncan K Brownsey, John J Kelly, Jeff Biernaskie, Peter B Dirks, Darren J Derksen, Steven J M Jones, Donna L Senger, Jennifer A Chan, Douglas J Mahoney, Daniel D De Carvalho, Marco Gallo.
      Self-renewal is a crucial property of glioblastoma cells that is enabled by the choreographed functions of chromatin regulators and transcription factors. Identifying targetable epigenetic mechanisms of self-renewal could therefore represent an important step toward developing effective treatments for this universally lethal cancer. Here we uncover an epigenetic axis of self-renewal mediated by the histone variant macroH2A2. With omics and functional assays deploying patient-derived in vitro and in vivo models, we show that macroH2A2 shapes chromatin accessibility at enhancer elements to antagonize transcriptional programs of self-renewal. macroH2A2 also sensitizes cells to small molecule-mediated cell death via activation of a viral mimicry response. Consistent with these results, our analyses of clinical cohorts indicate that high transcriptional levels of this histone variant are associated with better prognosis of high-grade glioma patients. Our results reveal a targetable epigenetic mechanism of self-renewal controlled by macroH2A2 and suggest additional treatment approaches for glioblastoma patients.
    DOI:  https://doi.org/10.1038/s41467-023-38919-2
  8. Cell Rep. 2023 May 26. pii: S2211-1247(23)00572-7. [Epub ahead of print]42(6): 112561
    Elevated FOXG1 in glioblastoma stem cells cooperates with Wnt/β-catenin to induce exit from quiescence.
    Faye L Robertson, Eoghan O'Duibhir, Ester Gangoso, Raul Bardini Bressan, Harry Bulstrode, Maria-Ángeles Marqués-Torrejón, Kirsty M Ferguson, Carla Blin, Vivien Grant, Neza Alfazema, Gillian M Morrison, Steven M Pollard.
      Glioblastoma (GBM) stem cells (GSCs) display phenotypic and molecular features reminiscent of normal neural stem cells and exhibit a spectrum of cell cycle states (dormant, quiescent, proliferative). However, mechanisms controlling the transition from quiescence to proliferation in both neural stem cells (NSCs) and GSCs are poorly understood. Elevated expression of the forebrain transcription factor FOXG1 is often observed in GBMs. Here, using small-molecule modulators and genetic perturbations, we identify a synergistic interaction between FOXG1 and Wnt/β-catenin signaling. Increased FOXG1 enhances Wnt-driven transcriptional targets, enabling highly efficient cell cycle re-entry from quiescence; however, neither FOXG1 nor Wnt is essential in rapidly proliferating cells. We demonstrate that FOXG1 overexpression supports gliomagenesis in vivo and that additional β-catenin induction drives accelerated tumor growth. These data indicate that elevated FOXG1 cooperates with Wnt signaling to support the transition from quiescence to proliferation in GSCs.
    Keywords:  CP: Cancer; CP: Stem cell research; FOXG1; GSK3 inhibitor; Wnt signaling; cell cycle; glioblastoma; neural stem cell; quiescence; β-catenin
    DOI:  https://doi.org/10.1016/j.celrep.2023.112561
  9. JCI Insight. 2023 May 30. pii: e160024. [Epub ahead of print]
    The SNP rs755622 is associated with immune activation in glioblastoma.
    Tyler J Alban, Matthew M Grabowski, Balint Otvos, Defne Bayik, Wesley Wang, Ajay H Zalavadia, Vladimir Makarav, Katie M Troike, Mary McGraw, Anja Rabljenovic, Adam Lauko, Chase Ka Neumann, Gustavo Roversi, Kristin A Waite, Gino Cioffi, Nirav Patil, Thuy T Tran, Kathleen McCortney, Alicia Steffens, C Marcela Diaz-Montero, J Mark Brown, Kathleen M Egan, Craig Horbinski, Jill S Barnholtz-Sloan, Prajwal Rajappa, Michael A Vogelbaum, Richard Bucala, Timothy A Chan, Manmeet S Ahluwalia, Justin D Lathia.
      Intratumoral heterogeneity is a defining hallmark of glioblastoma, driving drug resistant and ultimately recurrence. Many somatic drivers of microenvironmental change have been shown to affect this heterogeneity and ultimately treatment response. However, little is known about how germline mutations effect the tumoral microenvironment. Here, we find that the single-nucleotide polymorphism (SNP) rs755622 in promoter of the cytokine macrophage migration inhibitory factor (MIF), is associated with increased leukocyte infiltration in glioblastoma. Furthermore, we identified an association between rs755622 and lactotransferrin expression, which could also be used as a biomarker for immune-infiltrated tumors. These findings demonstrate that a germline SNP in the promoter region of MIF may impact the immune microenvironment and further reveals a link between lactotransferrin and immune activation.
    Keywords:  Brain cancer; Cellular immune response; Immunology; Immunotherapy; Oncology
    DOI:  https://doi.org/10.1172/jci.insight.160024
  10. Nat Protoc. 2023 May 29.
    Medulloblastoma and high-grade glioma organoids for drug screening, lineage tracing, co-culture and in vivo assay.
    Chiara Lago, Matteo Gianesello, Lucia Santomaso, Gloria Leva, Claudio Ballabio, Marica Anderle, Francesco Antonica, Luca Tiberi.
      Medulloblastoma and high-grade glioma represent the most aggressive and frequent lethal solid tumors affecting individuals during pediatric age. During the past years, several models have been established for studying these types of cancers. Human organoids have recently been shown to be a valid alternative model to study several aspects of brain cancer biology, genetics and test therapies. Notably, brain cancer organoids can be generated using genetically modified cerebral organoids differentiated from human induced pluripotent stem cells (hiPSCs). However, the protocols to generate them and their downstream applications are very rare. Here, we describe the protocols to generate cerebellum and forebrain organoids from hiPSCs, and the workflow to genetically modify them by overexpressing genes found altered in patients to finally produce cancer organoids. We also show detailed protocols to use medulloblastoma and high-grade glioma organoids for orthotopic transplantation and co-culture experiments aimed to study cell biology in vivo and in vitro, for lineage tracing to investigate the cell of origin and for drug screening. The protocol takes 60-65 d for cancer organoids generation and from 1-4 weeks for downstream applications. The protocol requires at least 3-6 months to become proficient in culturing hiPSCs, generating organoids and performing procedures on immunodeficient mice.
    DOI:  https://doi.org/10.1038/s41596-023-00839-2
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