bims-malgli Biomed News
on Biology of malignant gliomas
Issue of 2022‒09‒25
nineteen papers selected by
Oltea Sampetrean
Keio University
  1. Angiocrine extracellular vesicles impose mesenchymal reprogramming upon proneural glioma stem cells.
  2. Rodent Brain Tumor Models for Studies Focusing on Boron Neutron Capture Therapy.
  3. Elucidating the diversity of malignant mesenchymal states in glioblastoma by integrative analysis.
  4. The Chromatin-Oxygen Sensor Gene KDM5C Associates with Novel Hypoxia-Related Signatures in Glioblastoma Multiforme.
  5. H3.3-G34 mutations impair DNA repair and promote cGAS/STING-mediated immune responses in pediatric high-grade glioma models.
  6. Integrated longitudinal analysis of adult grade 4 diffuse gliomas with long-term relapse interval revealed upregulation of TGF-β signaling in recurrent tumors.
  7. Metabolic-imaging of human glioblastoma live tumors: A new precision-medicine approach to predict tumor treatment response early.
  8. GABP couples oncogene signaling to telomere regulation in TERT promoter mutant cancer.
  9. Distinct cell adhesion signature defines glioblastoma myeloid-derived suppressor cell subsets.
  10. EGFR, the Lazarus target for precision oncology in glioblastoma.
  11. Surgical Treatment of Glioblastoma: State-of-the-Art and Future Trends.
  12. Determining glioma cell invasion and proliferation in ex vivo organotypic mouse brain slices using whole-mount immunostaining and tissue clearing.
  13. Patient derived glioma stem cell spheroid reporter assays for live cell high content analysis.
  14. Natural coevolution of tumor and immunoenvironment in glioblastoma.
  15. Patterns of failure after radiation therapy in primary spinal high-grade gliomas: A single institutional analysis.
  16. PFKFB4 interacts with FBXO28 to promote HIF-1α signaling in glioblastoma.
  17. Gliomas lean on pyrimidines.
  18. Leveraging extrachromosomal DNA to fine-tune trials of targeted therapy for glioblastoma: opportunities and challenges.
  19. DNA methylation as a pharmacodynamic marker of glucocorticoid response and glioma survival.
  1. Nat Commun. 2022 Sep 19. 13(1): 5494
    Angiocrine extracellular vesicles impose mesenchymal reprogramming upon proneural glioma stem cells.
    Lata Adnani, Jordan Kassouf, Brian Meehan, Cristiana Spinelli, Nadim Tawil, Ichiro Nakano, Janusz Rak.
      Glioblastoma (GBM) is an incurable form of primary astrocytic brain tumor driven by glioma stem cell (GSC) compartment closely associated with the vascular niche. GSC phenotypes are heterogeneous and range from proneural to mesenchymal-like, the latter characterised by greater invasiveness. Here we document the secretory (angiocrine) role of endothelial cells and their derived extracellular vesicles (EVs) as drivers of proneural-to-mesenchymal reprogramming of GSCs. These changes involve activation of matrix metalloproteinases (MMPs) and NFκB, and inactivation of NOTCH, while altering responsiveness to chemotherapy and driving infiltrative growth in the brain. Our findings suggest that EV-mediated angiocrine interactions impact the nature of cellular stemness in GBM with implications for disease biology and therapy.
    DOI:  https://doi.org/10.1038/s41467-022-33235-7
  2. Cancer Biother Radiopharm. 2022 Sep 19.
    Rodent Brain Tumor Models for Studies Focusing on Boron Neutron Capture Therapy.
    Rolf F Barth, David E Carpenter.
      Background: Rodent brain tumor models have been very useful in advancing the treatment of glioblastomas. This review focuses on the four most widely used rodent brain tumor models: the C6, 9L, and F98 rat gliomas, and the GL261 murine glioma. All of these have been used in studies relating to boron neutron capture therapy. Conclusions: The most important of these studies were those using the 9L gliosarcoma, which led to the clinical use of boronophenylalanine, and the F98 glioma, which has been used for the preclinical evaluation of new boron delivery agents and methods of optimizing their delivery.
    Keywords:  BNCT; C6, 9L, and F98 rat gliomas; GL261 mouse glioma
    DOI:  https://doi.org/10.1089/cbr.2022.0041
  3. Genome Med. 2022 Sep 19. 14(1): 106
    Elucidating the diversity of malignant mesenchymal states in glioblastoma by integrative analysis.
    Rony Chanoch-Myers, Adi Wider, Mario L Suva, Itay Tirosh.
      BACKGROUND: Multiple glioblastoma studies have described a mesenchymal (MES) state, with each study defining the MES program by distinct sets of genes and highlighting distinct functional associations, including both immune activation and suppression. These variable descriptions complicate our understanding of the MES state and its implications. Here, we hypothesize that there is a range of glioma MES states, possibly reflecting distinct prior states in which a MES program can be induced, and/or distinct mechanisms that induce the MES states in those cells.METHODS: We integrated multiple published single-cell and bulk RNA sequencing datasets and MES signatures to define a core MES program that recurs across studies, as well as multiple function-specific MES signatures that vary across MES cells. We then examined the co-occurrence of these signatures and their associations with genetic and microenvironmental features.
    RESULTS: Based on co-occurrence of MES signatures, we found three main variants of MES states: hypoxia-related (MES-Hyp), astrocyte-related (MES-Ast), and an intermediate state. Notably, the MES states are differentially associated with genetic and microenvironmental features. MES-Hyp is preferentially associated with NF1 deletion, overall macrophage abundance, a high macrophage/microglia ratio, and M2-related macrophages, consistent with previous studies that associated MES with immune suppression. In contrast, MES-Ast is associated with T cell abundance and cytotoxicity, consistent with immune activation through expression of MHC-I/II.
    CONCLUSIONS: Diverse MES states occur in glioblastoma. These states share a subset of core genes but differ primarily in their association with hypoxia vs. astrocytic expression programs, and with immune suppression vs. activation, respectively.
    DOI:  https://doi.org/10.1186/s13073-022-01109-8
  4. Int J Mol Sci. 2022 Sep 06. pii: 10250. [Epub ahead of print]23(18):
    The Chromatin-Oxygen Sensor Gene KDM5C Associates with Novel Hypoxia-Related Signatures in Glioblastoma Multiforme.
    Denise Drongitis, Lucia Verrillo, Pasqualino De Marinis, Pasquale Orabona, Agnese Caiola, Giacinto Turitto, Alessandra Alfieri, Sara Bruscella, Marisa Gentile, Vania Moriello, Ettore Sannino, Ines Di Muccio, Valerio Costa, Maria Giuseppina Miano, Alberto de Bellis.
      Glioblastoma multiforme (GBM) is a fatal brain tumor without effective drug treatment. In this study, we highlight, for the first time, the contribution of chromatin remodeling gene Lysine (K)-specific demethylase 5C (KDM5C) in GBM via an extensive analysis of clinical, expression, and functional data, integrated with publicly available omic datasets. The expression analysis on GBM samples (N = 37) revealed two informative subtypes, namely KDM5CHigh and KDM5CLow, displaying higher/lower KDM5C levels compared to the controls. The former subtype displays a strong downregulation of brain-derived neurotrophic factor (BDNF)-a negative KDM5C target-and a robust overexpression of hypoxia-inducible transcription factor-1A (HIF1A) gene, a KDM5C modulator. Additionally, a significant co-expression among the prognostic markers HIF1A, Survivin, and p75 was observed. These results, corroborated by KDM5C overexpression and hypoxia-related functional assays in T98G cells, suggest a role for the HIF1A-KDM5C axis in the hypoxic response in this tumor. Interestingly, fluorescence-guided surgery on GBM sections further revealed higher KDM5C and HIF1A levels in the tumor rim niche compared to the adjacent tumor margin, indicating a regionally restricted hyperactivity of this regulatory axis. Analyzing the TCGA expression and methylation data, we found methylation changes between the subtypes in the genes, accounting for the hypoxia response, stem cell differentiation, and inflammation. High NANOG and IL6 levels highlight a distinctive stem cell-like and proinflammatory signature in the KDM5CHigh subgroup and GBM niches. Taken together, our results indicate HIF1A-KDM5C as a new, relevant cancer axis in GBM, opening a new, interesting field of investigation based on KDM5C as a potential therapeutic target of the hypoxic microenvironment in GBM.
    Keywords:  5-aminolevulinic acid fluorescence-guided surgery (5-ALA FGS); GBM with epilepsy; HIF1A-KDM5C axis; KDM5C; glioblastoma multiforme; hypoxic microenvironment
    DOI:  https://doi.org/10.3390/ijms231810250
  5. J Clin Invest. 2022 Sep 20. pii: e154229. [Epub ahead of print]
    H3.3-G34 mutations impair DNA repair and promote cGAS/STING-mediated immune responses in pediatric high-grade glioma models.
    Santiago Haase, Kaushik Banerjee, Anzar A Mujeeb, Carson S Hartlage, Fernando M Nunez, Felipe J Nuñez, Mahmoud S Alghamri, Padma Kadiyala, Stephen Carney, Marcus Barissi, Ayman W Taher, Emily K Brumley, Sarah Thompson, Justin T Dreyer, Caitlin T Alindogan, Maria B Garcia-Fabiani, Andrea Comba, Sriram Venneti, Visweswaran Ravikumar, Carl Koschmann, Angel M Carcaboso, Maria Vinci, Arvind Rao, Jennifer S Yu, Pedro R Lowenstein, Maria G Castro.
      Pediatric high-grade gliomas (pHGGs) are the leading cause of cancer-related deaths in children in the USA. Sixteen percent of hemispheric pediatric and young adult HGGs encode Gly34Arg/Val substitutions in the histone H3.3 (H3.3-G34R/V). The mechanisms by which H3.3-G34R/V drive malignancy and therapeutic resistance in pHGGs remain unknown. Using a syngeneic, genetically engineered mouse model (GEMM) and human pHGG cells encoding H3.3-G34R, we demonstrate that this mutation leads to downregulation of the DNA repair pathways. This leads to enhanced susceptibility to DNA damage and inhibition of the DNA damage response (DDR). We demonstrate that genetic instability resulting from improper DNA repair in G34R-mutant pHGG leads to accumulation of extrachromosomal DNA, which activates the cGAS-STING pathway, inducing the release of immune-stimulatory cytokines. We treated H3.3-G34R pHGG-bearing mice with a combination of radiotherapy (RT) and DNA damage response inhibitors (DDRi) (i.e., the blood-brain barrier permeable PARP inhibitor, pamiparib, and the cell cycle checkpoint CHK1/2 inhibitor, AZD7762), and these combinations resulted in approximately 50% long-term survivors. Moreover, the addition of a STING agonist (diABZl) enhanced the therapeutic efficacy of these treatments. Long-term survivors developed immunological memory, preventing pHGG growth upon rechallenge. These results demonstrate that DDRi and STING agonists in combination with RT induce immune-mediated therapeutic efficacy in G34-mutant pHGG.
    Keywords:  Brain cancer; DNA repair; Drug therapy; Oncology; Therapeutics
    DOI:  https://doi.org/10.1172/JCI154229
  6. Neuro Oncol. 2022 Sep 17. pii: noac220. [Epub ahead of print]
    Integrated longitudinal analysis of adult grade 4 diffuse gliomas with long-term relapse interval revealed upregulation of TGF-β signaling in recurrent tumors.
    SOCIBP consortium
      BACKGROUND: Adult-type diffuse gliomas, CNS WHO grade 4 are the most aggressive primary brain tumors and represent a particular challenge of therapeutic intervention.METHODS: In a single-center retrospective study of matched pairs of initial and post-therapeutic glioma cases with a recurrence period greater than one year, we performed whole exome sequencing combined with mRNA and microRNA expression profiling to identify processes that are altered in recurrent gliomas.
    RESULTS: Mutational analysis of recurrent gliomas revealed early branching evolution in seventy-five percent of patients. High plasticity was confirmed at the mRNA and miRNA levels. SBS1 signature was reduced and SBS11 was elevated, demonstrating the effect of alkylating agent therapy on the mutational landscape. There was no evidence for secondary genomic alterations driving therapy resistance. ALK7/ACVR1C and LTBP1 were upregulated, whereas LEFTY2 was downregulated, pointing towards enhanced Tumor Growth Factor β (TGF-β) signaling in recurrent gliomas. Consistently, altered microRNA expression profiles pointed towards enhanced Nuclear Factor Kappa B and Wnt signaling that, cooperatively with TGF-β, induces epithelial to mesenchymal transition (EMT), migration and stemness. TGF-β-induced expression of pro-apoptotic proteins and repression of anti-apoptotic proteins were uncoupled in the recurrent tumor.
    CONCLUSIONS: Our results suggest an important role of TGF-β signaling in recurrent gliomas. This may have clinical implication, since TGF-β inhibitors have entered clinical phase studies and may potentially be used in combination therapy to interfere with chemoradiation resistance. Recurrent gliomas show high incidence of early branching evolution. High tumor plasticity is confirmed at the level of microRNA and mRNA expression profiles.
    Keywords:  Glioblastoma; TGF-β signaling; longitudinal analysis; miRNA; tumor evolution
    DOI:  https://doi.org/10.1093/neuonc/noac220
  7. Front Oncol. 2022 ;12 969812
    Metabolic-imaging of human glioblastoma live tumors: A new precision-medicine approach to predict tumor treatment response early.
    Mariangela Morelli, Francesca Lessi, Serena Barachini, Romano Liotti, Nicola Montemurro, Paolo Perrini, Orazio Santo Santonocito, Carlo Gambacciani, Matija Snuderl, Francesco Pieri, Filippo Aquila, Azzurra Farnesi, Antonio Giuseppe Naccarato, Paolo Viacava, Francesco Cardarelli, Gianmarco Ferri, Paul Mulholland, Diego Ottaviani, Fabiola Paiar, Gaetano Liberti, Francesco Pasqualetti, Michele Menicagli, Paolo Aretini, Giovanni Signore, Sara Franceschi, Chiara Maria Mazzanti.
      Background: Glioblastoma (GB) is the most severe form of brain cancer, with a 12-15 month median survival. Surgical resection, temozolomide (TMZ) treatment, and radiotherapy remain the primary therapeutic options for GB, and no new therapies have been introduced in recent years. This therapeutic standstill is primarily due to preclinical approaches that do not fully respect the complexity of GB cell biology and fail to test efficiently anti-cancer treatments. Therefore, better treatment screening approaches are needed. In this study, we have developed a novel functional precision medicine approach to test the response to anticancer treatments in organoids derived from the resected tumors of glioblastoma patients.Methods: GB organoids were grown for a short period of time to prevent any genetic and morphological evolution and divergence from the tumor of origin. We chose metabolic imaging by NAD(P)H fluorescence lifetime imaging microscopy (FLIM) to predict early and non-invasively ex-vivo anti-cancer treatment responses of GB organoids. TMZ was used as the benchmark drug to validate the approach. Whole-transcriptome and whole-exome analyses were performed to characterize tumor cases stratification.
    Results: Our functional precision medicine approach was completed within one week after surgery and two groups of TMZ Responder and Non-Responder tumors were identified. FLIM-based metabolic tumor stratification was well reflected at the molecular level, confirming the validity of our approach, highlighting also new target genes associated with TMZ treatment and identifying a new 17-gene molecular signature associated with survival. The number of MGMT gene promoter methylated tumors was higher in the responsive group, as expected, however, some non-methylated tumor cases turned out to be nevertheless responsive to TMZ, suggesting that our procedure could be synergistic with the classical MGMT methylation biomarker.
    Conclusions: For the first time, FLIM-based metabolic imaging was used on live glioblastoma organoids. Unlike other approaches, ex-vivo patient-tailored drug response is performed at an early stage of tumor culturing with no animal involvement and with minimal tampering with the original tumor cytoarchitecture. This functional precision medicine approach can be exploited in a range of clinical and laboratory settings to improve the clinical management of GB patients and implemented on other cancers as well.
    Keywords:  FLIM (fluorescence lifetime imaging microscopy); drug response assay; glioblastoma; metabolic imaging; predictive model
    DOI:  https://doi.org/10.3389/fonc.2022.969812
  8. Cell Rep. 2022 Sep 20. pii: S2211-1247(22)01172-X. [Epub ahead of print]40(12): 111344
    GABP couples oncogene signaling to telomere regulation in TERT promoter mutant cancer.
    Andrew M McKinney, Radhika Mathur, Nicholas O Stevers, Annette M Molinaro, Susan M Chang, Joanna J Phillips, Joseph F Costello.
      Telomerase activation counteracts senescence and telomere erosion caused by uncontrolled proliferation. Epidermal growth factor receptor (EGFR) amplification drives proliferation while telomerase reverse transcriptase promoter (TERTp) mutations underlie telomerase reactivation through recruitment of GA-binding protein (GABP). EGFR amplification and TERTp mutations typically co-occur in glioblastoma, the most common and aggressive primary brain tumor. To determine if these two frequent alterations driving proliferation and immortality are functionally connected, we combine analyses of copy number, mRNA, and protein data from tumor tissue with pharmacologic and genetic perturbations. We demonstrate that proliferation arrest decreases TERT expression in a GABP-dependent manner and elucidate a critical proliferation-to-immortality pathway from EGFR to TERT expression selectively from the mutant TERTp through activation of AMP-mediated kinase (AMPK) and GABP upregulation. EGFR-AMPK signaling promotes telomerase activity and maintains telomere length. These results define how the tumor cell immortality mechanism keeps pace with persistent oncogene signaling and cell cycling.
    Keywords:  CNS cancer; CP: Cancer; EGFR; GABP; TERT promoter mutations; glioblastoma; telomere maintenance
    DOI:  https://doi.org/10.1016/j.celrep.2022.111344
  9. Cancer Res. 2022 09 20. pii: CAN-21-3840. [Epub ahead of print]
    Distinct cell adhesion signature defines glioblastoma myeloid-derived suppressor cell subsets.
    Defne Bayik, Cynthia F Bartels, Katreya Lovrenert, Dionysios C Watson, Duo Zhang, Kristen Kay, Juyeun Lee, Adam Lauko, Sadie Johnson, Alice Lo, Daniel J Silver, Mary McGraw, Matthew M Grabowski, Alireza M Mohammadi, Filippo Veglia, Yi Fan, Michael A Vogelbaum, Peter C Scacheri, Justin D Lathia.
      In multiple types of cancer, an increased frequency in myeloid-derived suppressor cells (MDSC) is associated with worse outcomes and poor therapeutic response. In the glioblastoma (GBM) microenvironment, monocytic (m) MDSCs represent the predominant subset. However, the molecular basis of mMDSC enrichment in the tumor microenvironment compared to granulocytic (g) MDSCs has yet to be determined. Here we performed the first broad epigenetic profiling of MDSC subsets to define underlying cell-intrinsic differences in behavior and found that enhanced gene accessibility of cell adhesion programs in mMDSCs is linked to their tumor-accelerating ability in GBM models upon adoptive transfer. Mouse and human mMDSCs expressed higher levels of integrin β1 and dipeptidyl peptidase-4 (DPP-4) compared to gMDSCs as part of an enhanced cell adhesion signature. Integrin β1 blockade abrogated the tumor-promoting phenotype of mMDSCs and altered the immune profile in the tumor microenvironment, while treatment with a DPP-4 inhibitor extended survival in preclinical GBM models. Targeting DPP-4 in mMDSCs reduced pERK signaling and their migration towards tumor cells. These findings uncover a fundamental difference in the molecular basis of MDSC subsets and suggest that integrin β1 and DPP-4 represent putative immunotherapy targets to attenuate myeloid cell-driven immune suppression in GBM.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-21-3840
  10. Neuro Oncol. 2022 Sep 19. pii: noac204. [Epub ahead of print]
    EGFR, the Lazarus target for precision oncology in glioblastoma.
    Benjamin Lin, Julia Ziebro, Erin Smithberger, Kasey R Skinner, Eva Zhao, Timothy F Cloughesy, Zev A Binder, Donald M O'Rourke, David A Nathanson, Frank B Furnari, C Ryan Miller.
      The Lazarus effect is a rare condition that happens when someone seemingly dead shows signs of life. The epidermal growth factor receptor (EGFR) represents a target in the fatal neoplasm glioblastoma (GBM) that through a series of negative clinical trials has prompted a vocal subset of the neuro-oncology community to declare this target dead. However, an argument can be made that the core tenets of precision oncology were overlooked in the initial clinical enthusiasm over EGFR as a therapeutic target in GBM. Namely, the wrong drugs were tested on the wrong patients at the wrong time. Furthermore, new insights into the biology of EGFR in GBM vis-à-vis other EGFR-driven neoplasms, such as non-small cell lung cancer, and development of novel GBM-specific EGFR therapeutics resurrects this target for future studies. Here, we will examine the distinct EGFR biology in GBM, how it exacerbates the challenge of treating a CNS neoplasm, how these unique challenges have influenced past and present EGFR-targeted therapeutic design and clinical trials, and what adjustments are needed to therapeutically exploit EGFR in this devastating disease.
    Keywords:  Biological therapy; glioblastoma; molecular heterogeneity; precision oncology; tyrosine kinase inhibitors
    DOI:  https://doi.org/10.1093/neuonc/noac204
  11. J Clin Med. 2022 Sep 13. pii: 5354. [Epub ahead of print]11(18):
    Surgical Treatment of Glioblastoma: State-of-the-Art and Future Trends.
    Arthur H A Sales, Jürgen Beck, Oliver Schnell, Christian Fung, Bernhard Meyer, Jens Gempt.
      Glioblastoma (GBM) is a highly aggressive disease and is associated with poor prognosis despite treatment advances in recent years. Surgical resection of tumor remains the main therapeutic option when approaching these patients, especially when combined with adjuvant radiochemotherapy. In the present study, we conducted a comprehensive literature review on the state-of-the-art and future trends of the surgical treatment of GBM, emphasizing topics that have been the object of recent study.
    Keywords:  extent of resection; glioblastoma; intraoperative fluorescence; intraoperative magnetic resonance imaging; residual tumor volume; surgery
    DOI:  https://doi.org/10.3390/jcm11185354
  12. STAR Protoc. 2022 Sep 21. pii: S2666-1667(22)00583-4. [Epub ahead of print]3(4): 101703
    Determining glioma cell invasion and proliferation in ex vivo organotypic mouse brain slices using whole-mount immunostaining and tissue clearing.
    Jessy V van Asperen, Emma J van Bodegraven, Pierre A J T Robe, Elly M Hol.
      The ex vivo organotypic brain slice invasion model is commonly used to study the growth dynamics of gliomas, primary brain tumors that are known for their invasive behavior. Here, we describe a protocol where the ex vivo organotypic mouse brain slice invasion model is combined with whole-mount immunostaining, tissue clearing, and 3D reconstruction, to visualize and quantify the invasion of glioma cells. In addition, we describe an approach to determine the proliferation rate of the cells within this model. For complete details on the use and execution of this protocol, please refer to Uceda-Castro et al. (2022).
    Keywords:  Antibody; Cancer; Cell biology; Microscopy; Neuroscience
    DOI:  https://doi.org/10.1016/j.xpro.2022.101703
  13. SLAS Discov. 2022 Sep 15. pii: S2472-5552(22)13694-4. [Epub ahead of print]
    Patient derived glioma stem cell spheroid reporter assays for live cell high content analysis.
    Jayne Culley, Peter W Nagle, John C Dawson, Neil O Carragher.
      Three dimensional models of cell culture enables researchers to recreate aspects of tumour biology not replicated by traditional two dimensional techniques. Here we describe a protocol to enable automated high throughput phenotypic profiling across panels of patient derived glioma stem cell spheroid models. We demonstrate the use of both live/dead cell end-points and monitor the dynamic changes in the cell cycle using cell lines expressing the FUCCI cell cycle reporter. Together, these assays provide additional insight into the mechanism of action of compound treatments over traditional cell viability assay endpoints.
    Keywords:  3-dimensional; Glioblastoma; Spheroid; cell cycle; drug discovery
    DOI:  https://doi.org/10.1016/j.slasd.2022.09.002
  14. Cancer Discov. 2022 Sep 19. pii: CD-22-0196. [Epub ahead of print]
    Natural coevolution of tumor and immunoenvironment in glioblastoma.
    Lingxiang Wu, Wei Wu, Junxia Zhang, Zheng Zhao, Liangyu Li, Mengyan Zhu, Min Wu, Fan Wu, Fengqi Zhou, Yuxin Du, Rui-Chao Chai, Wei Zhang, Xiaoguang Qiu, Quanzhong Liu, Ziyu Wang, Jie Li, Kening Li, Apeng Chen, Yinan Jiang, Xiangwei Xiao, Han Zou, Rashmi Srivastava, Tingting Zhang, Yun Cai, Yuan Liang, Bin Huang, Ruohan Zhang, Fan Lin, Lang Hu, Xiuxing Wang, Xu Qian, Sali Lv, Baoli Hu, Siyuan Zheng, Zhibin Hu, Hongbing Shen, Yongping You, Roel Gw Verhaak, Tao Jiang, Qianghu Wang.
      IDH wild-type glioblastoma (GBM) has a dismal prognosis. A better understanding of tumor evolution holds the key to developing more effective treatment. Here we study glioblastoma's natural evolutionary trajectory by using rare, multifocal samples. We sequenced 61,062 single cells from eight multifocal IDH wild-type primary GBMs and defined a natural evolution signature (NES) of the tumor. We show that the NES significantly associates with the activation of transcription factors that regulate brain development, including MYBL2 and FOSL2. Hypoxia is involved in inducing NES-transition potentially via activation of the HIF1A-FOSL2 axis. High NES tumor cells could recruit and polarize bone marrow-derived macrophages through activation of the FOSL2-ANXA1-FPR1/3 axis. These polarized macrophages can efficiently suppress T cell activity and accelerate NES-transition in tumor cells. Moreover, The polarized macrophages could upregulate CCL2 to induce tumor cell migration.
    DOI:  https://doi.org/10.1158/2159-8290.CD-22-0196
  15. Neurooncol Adv. 2022 Jan-Dec;4(1):4(1): vdac129
    Patterns of failure after radiation therapy in primary spinal high-grade gliomas: A single institutional analysis.
    Rituraj Upadhyay, Swapnil Khose, Halyna Pokhylevych, Arnold C Paulino, Mary Frances McAleer, Amol Ghia, Jing Li, Debra Nana Yeboa, Monica Loghin, Rebecca Harrison, Barbara O'Brien, Carlos Kamiya-Matsuoka, John De Groot, Vinay K Puduvalli, Claudio Tatsui, Christopher Alvarez-Breckenridge, Sujit Prabhu, Larry Rhines, Wafik Zaky, Frank Lin, Jeffery S Weinberg, Gregory Fuller, David I Sandberg, Jason Michael Johnson, Susan L McGovern.
      Background: Primary spinal high-grade gliomas (S-HGG) are rare aggressive tumors; radiation therapy (RT) often plays a dominant role in management. We conducted a single-institution retrospective review to study the clinicopathological features and management of S-HGGs.Methods: Patients with biopsy-proven S-HGG who received RT from 2001 to 2020 were analyzed for patient, tumor, and treatment characteristics. Kaplan-Meier estimates were used for survival analyses.
    Results: Twenty-nine patients were identified with a median age of 25.9 years (range 1-74 y). Four patients had GTR while 25 underwent subtotal resection or biopsy. All patients were IDH wildtype and MGMT-promoter unmethylated, where available. H3K27M mutation was present in 5 out of 10 patients tested, while one patient harbored p53 mutation. Median RT dose was 50.4 Gy (range 39.6-54 Gy) and 65% received concurrent chemotherapy, most commonly temozolomide. Twenty-three (79%) of patients had documented recurrence. Overall, 16 patients relapsed locally, 10 relapsed in the brain and 8 developed leptomeningeal disease; only 8 had isolated local relapse. Median OS from diagnosis was 21.3 months and median PFS was 9.7 months. On univariate analysis, age, gender, GTR, grade, RT modality, RT dose and concurrent chemotherapy did not predict for survival. Patients with H3K27M mutation had a poorer PFS compared to those without mutation (10.1 m vs 45.1 m) but the difference did not reach statistical significance (P = .26).
    Conclusions: The prognosis of patients with spinal HGGs remains poor with two-thirds of the patients developing distant recurrence despite chemoradiation. Survival outcomes were similar in patients ≤ 29 years compared to adults > 29 years. A better understanding of the molecular drivers of spinal HGGs is needed to develop more effective treatment options.
    Keywords:  high-grade glioma; proton therapy; radiation; spinal glioma
    DOI:  https://doi.org/10.1093/noajnl/vdac129
  16. Oncogenesis. 2022 Sep 17. 11(1): 57
    PFKFB4 interacts with FBXO28 to promote HIF-1α signaling in glioblastoma.
    Emma Phillips, Jörg Balss, Frederic Bethke, Stefan Pusch, Stefan Christen, Thomas Hielscher, Martina Schnölzer, Michael N C Fletcher, Antje Habel, Claudia Tessmer, Lisa-Marie Brenner, Mona Göttmann, David Capper, Christel Herold-Mende, Andreas von Deimling, Sarah-Maria Fendt, Violaine Goidts.
      Glioblastoma is a highly aggressive brain tumor for which there is no cure. The metabolic enzyme 6-Phosphofructo-2-Kinase/Fructose-2,6-Biphosphatase 4 (PFKFB4) is essential for glioblastoma stem-like cell (GSC) survival but its mode of action is unclear. Understanding the role of PFKFB4 in tumor cell survival could allow it to be leveraged in a cancer therapy. Here, we show the importance of PFKFB4 for glioblastoma growth in vivo in an orthotopic patient derived mouse model. In an evaluation of patient tumor samples of different cancer entities, PFKFB4 protein was found to be overexpressed in prostate, lung, colon, mammary and squamous cell carcinoma, with expression level correlating with tumor grade. Gene expression profiling in PFKFB4-silenced GSCs revealed a downregulation of hypoxia related genes and Western blot analysis confirmed a dramatic reduction of HIF (hypoxia inducible factor) protein levels. Through mass spectrometric analysis of immunoprecipitated PFKFB4, we identified the ubiquitin E3 ligase, F-box only protein 28 (FBXO28), as a new interaction partner of PFKFB4. We show that PFKFB4 regulates the ubiquitylation and subsequent proteasomal degradation of HIF-1α, which is mediated by the ubiquitin ligase activity of FBXO28. This newly discovered function of PFKFB4, coupled with its cancer specificity, provides a new strategy for inhibiting HIF-1α in cancer cells.
    DOI:  https://doi.org/10.1038/s41389-022-00433-3
  17. Nat Rev Cancer. 2022 Sep 21.
    Gliomas lean on pyrimidines.
    Joseph Willson.
      
    DOI:  https://doi.org/10.1038/s41568-022-00515-9
  18. Nat Rev Clin Oncol. 2022 Sep 21.
    Leveraging extrachromosomal DNA to fine-tune trials of targeted therapy for glioblastoma: opportunities and challenges.
    Imran Noorani, Paul S Mischel, Charles Swanton.
      Glioblastoma evolution is facilitated by intratumour heterogeneity, which poses a major hurdle to effective treatment. Evidence indicates a key role for oncogene amplification on extrachromosomal DNA (ecDNA) in accelerating tumour evolution and thus resistance to treatment, particularly in glioblastomas. Oncogenes contained within ecDNA can reach high copy numbers and expression levels, and their unequal segregation can result in more rapid copy number changes in response to therapy than is possible through natural selection of intrachromosomal genomic loci. Notably, targeted therapies inhibiting oncogenic pathways have failed to improve glioblastoma outcomes. In this Perspective, we outline reasons for this disappointing lack of clinical translation and present the emerging evidence implicating ecDNA as an important driver of tumour evolution. Furthermore, we suggest that through detection of ecDNA, patient selection for clinical trials of novel agents can be optimized to include those most likely to benefit based on current understanding of resistance mechanisms. We discuss the challenges to successful translation of this approach, including accurate detection of ecDNA in tumour tissue with novel technologies, development of faithful preclinical models for predicting the efficacy of novel agents in the presence of ecDNA oncogenes, and understanding the mechanisms of ecDNA formation during cancer evolution and how they could be attenuated therapeutically. Finally, we evaluate the feasibility of routine ecDNA characterization in the clinic and how this process could be integrated with other methods of molecular stratification to maximize the potential for clinical translation of precision medicines.
    DOI:  https://doi.org/10.1038/s41571-022-00679-1
  19. Nat Commun. 2022 Sep 20. 13(1): 5505
    DNA methylation as a pharmacodynamic marker of glucocorticoid response and glioma survival.
    J K Wiencke, Annette M Molinaro, Gayathri Warrier, Terri Rice, Jennifer Clarke, Jennie W Taylor, Margaret Wrensch, Helen Hansen, Lucie McCoy, Emily Tang, Stan J Tamaki, Courtney M Tamaki, Emily Nissen, Paige Bracci, Lucas A Salas, Devin C Koestler, Brock C Christensen, Ze Zhang, Karl T Kelsey.
      Assessing individual responses to glucocorticoid drug therapies that compromise immune status and affect survival outcomes in neuro-oncology is a great challenge. Here we introduce a blood-based neutrophil dexamethasone methylation index (NDMI) that provides a measure of the epigenetic response of subjects to dexamethasone. This marker outperforms conventional approaches based on leukocyte composition as a marker of glucocorticoid response. The NDMI is associated with low CD4 T cells and the accumulation of monocytic myeloid-derived suppressor cells and also serves as prognostic factor in glioma survival. In a non-glioma population, the NDMI increases with a history of prednisone use. Therefore, it may also be informative in other conditions where glucocorticoids are employed. We conclude that DNA methylation remodeling within the peripheral immune compartment is a rich source of clinically relevant markers of glucocorticoid response.
    DOI:  https://doi.org/10.1038/s41467-022-33215-x
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