bims-malgli Biomed News
on Biology of malignant gliomas
Issue of 2023–04–30
ten papers selected by
Oltea Sampetrean, Keio University
  1. Crosstalk between microglia and neural stem cells influences the relapse of glioblastoma in GBM immunological microenvironment.
  2. Chi3l1 is a modulator of glioma stem cell states and a therapeutic target in glioblastoma.
  3. Postoperative risk of IDH mutant glioma-associated seizures and their potential management with IDH mutant inhibitors.
  4. Targeting SWI/SNF ATPases in H3.3K27M diffuse intrinsic pontine gliomas.
  5. NF-κB/p52 augments ETS1 binding genome-wide to promote glioma progression.
  6. Self-assembling paclitaxel-mediated stimulation of tumor-associated macrophages for postoperative treatment of glioblastoma.
  7. Phase II Investigation of TVB-2640 (denifanstat) with Bevacizumab in Patients with First Relapse High-Grade Astrocytoma.
  8. The genomic landscape of familial glioma.
  9. Mitotic index is (still) important for grading IDH-mutant astrocytoma.
  10. GTP signaling links metabolism, DNA repair, and responses to genotoxic stress.
  1. Clin Immunol. 2023 Apr 21. pii: S1521-6616(23)00112-2. [Epub ahead of print] 109333
    Crosstalk between microglia and neural stem cells influences the relapse of glioblastoma in GBM immunological microenvironment.
    Xingliang Dai, Lei Ye, Huaixu Li, Xuchen Dong, Haotiao Tian, Peng Gao, Jun Dong, Hongwei Cheng.
      Interactions between immunocytes and Neural Stem Cells (NSCs) in glioblastoma multiforme still remains unclear. Here, microglial cells and NSCs in peri-tumoral tissue were analyzed via single-cell whole-transcriptome sequencing. Results showed that two clusters of putative NSCs (the EGFR+BCAN+ cell cluster, and the FABPT+H19+ cell cluster) exhibited immune-related functions. Two clusters of putative microglia (the XIST+PDK4+ and APOC1+CCL3+ cell clusters) exhibited the function of glial cell activation. The results of ligand receptor network analysis disclosed significant interactions between the APOC1+CCL3+ microglia and the NSCs. Correlation analysis on the overall survival (OS) and relapse-free survival (RFS) with 102 potential molecular targets in the TCGA database showed that a much larger number of molecules were correlated with RFS than with OS (34.31% vs. 8.82%), nine of them were validated in clinical specimens. In conclusion, crosstalk between APOC1+CCL3+ microglia and multiple molecule-labeled NSCs distal to the tumor core play certain roles on the recurrence of GBM.
    Keywords:  Glioblastoma multiforme; Immunological microenvironment; Recurrence; Single-cell RNA sequencing
    DOI:  https://doi.org/10.1016/j.clim.2023.109333
  2. Cancer Res. 2023 Apr 27. pii: CAN-21-3629. [Epub ahead of print]
    Chi3l1 is a modulator of glioma stem cell states and a therapeutic target in glioblastoma.
    Charlotte Guetta-Terrier, David Karambizi, Bedia Akosman, John P Zepecki, Jia-Shu Chen, Suchitra Kamle, J Eduardo Fajardo, Andras Fiser, Ritambhara Singh, Steven A Toms, Chun Geun Lee, Jack A Elias, Nikos Tapinos.
      Chi3l1 (chitinase 3-like 1) is a secreted protein that is highly expressed in glioblastoma. Here, we show that Chi3l1 alters the state of glioma stem cells (GSCs) to support tumor growth. Exposure of patient-derived GSCs to Chi3l1 reduced the frequency of CD133+SOX2+ cells and increased the CD44+Chi3l1+ cells. Chi3l1 bound to CD44 and induced phosphorylation and nuclear translocation of β-catenin, Akt and STAT3. Single cell RNA-seq and RNA velocity following incubation of GSCs with Chi3l1 showed significant changes in GSC state dynamics driving GSCs towards a mesenchymal expression profile and reducing transition probabilities towards terminal cellular states. ATAC-seq revealed that Chi3l1 increases accessibility of promoters containing a MAZ transcription factor footprint. Inhibition of MAZ downregulated a set of genes with high expression in cellular clusters that exhibit significant cell state transitions after treatment with Chi3l1, and MAZ deficiency rescued the Chi3l-induced increase of GSC self-renewal. Finally, targeting Chi3l1 in vivo with a blocking antibody inhibited tumor growth and increased the probability of survival. Overall, this work suggests that Chi3l1 interacts with CD44 on the surface of glioma stem cells to induce Akt/β-catenin signaling and MAZ transcriptional activity, which in turn upregulates CD44 expression in a pro-mesenchymal feed-forward loop. The role of Chi3l1 in regulating cellular plasticity confers a targetable vulnerability to glioblastoma.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-21-3629
  3. J Clin Invest. 2023 Apr 27. pii: e168035. [Epub ahead of print]
    Postoperative risk of IDH mutant glioma-associated seizures and their potential management with IDH mutant inhibitors.
    Michael Drumm, Wenxia Wang, Thomas K Sears, Kirsten Bell-Burdett, Rodrigo Javier, Kristen Y Cotton, Brynna T Webb, Kayla T Byrne, Dusten Unruh, Vineeth Thirunavu, Jordain Walshon, Alicia Steffens, Kathleen McCortney, Rimas V Lukas, Joanna J Phillips, Esraa Mohamed, John D Finan, Lucas Santana-Santos, Amy B Heimberger, Colin K Franz, Jonathan E Kurz, Jessica W Templer, Geoffrey T Swanson, Craig Horbinski.
      Seizures are a frequent complication of adult-type diffuse gliomas, and are often difficult to control with medications. Gliomas with mutations in isocitrate dehydrogenase 1 or 2 (IDHmut) are more likely than IDH wild-type (IDHwt) gliomas to cause seizures as part of their initial clinical presentation. However, whether IDHmut is also associated with seizures during the remaining disease course, and whether IDHmut inhibitors can reduce seizure risk, are unclear. Clinical multivariable analyses showed that preoperative seizures, glioma location, extent of resection, and glioma molecular subtype (including IDHmut status) all contribute to postoperative seizure risk in adult-type diffuse glioma patients, and that postoperative seizures are often associated with tumor recurrence. Experimentally, the metabolic product of IDHmut, D-2-hydroxyglutarate, rapidly synchronizes neuronal spike firing in a seizure-like manner, but only when nonneoplastic glial cells are present. In vitro and in vivo models can recapitulate IDHmut glioma-associated seizures, and IDHmut inhibitors currently being evaluated in glioma clinical trials inhibit seizures in those models, independent of their effects on glioma growth. These data show that postoperative seizure risk in adult-type diffuse gliomas varies in large part by molecular subtype, and that IDHmut inhibitors could play a key role in mitigating such risk in IDHmut glioma patients.
    Keywords:  Brain cancer; Epilepsy; Neuroscience; Oncology; Seizures
    DOI:  https://doi.org/10.1172/JCI168035
  4. Proc Natl Acad Sci U S A. 2023 May 02. 120(18): e2221175120
    Targeting SWI/SNF ATPases in H3.3K27M diffuse intrinsic pontine gliomas.
    Mateus Mota, Stefan R Sweha, Matt Pun, Siva Kumar Natarajan, Yujie Ding, Chan Chung, Debra Hawes, Fusheng Yang, Alexander R Judkins, Susanta Samajdar, Xuhong Cao, Lanbo Xiao, Abhijit Parolia, Arul M Chinnaiyan, Sriram Venneti.
      Diffuse midline gliomas (DMGs) including diffuse intrinsic pontine gliomas (DIPGs) bearing lysine-to-methionine mutations in histone H3 at lysine 27 (H3K27M) are lethal childhood brain cancers. These tumors harbor a global reduction in the transcriptional repressive mark H3K27me3 accompanied by an increase in the transcriptional activation mark H3K27ac. We postulated that H3K27M mutations, in addition to altering H3K27 modifications, reprogram the master chromatin remodeling switch/sucrose nonfermentable (SWI/SNF) complex. The SWI/SNF complex can exist in two main forms termed BAF and PBAF that play central roles in neurodevelopment and cancer. Moreover, BAF antagonizes PRC2, the main enzyme catalyzing H3K27me3. We demonstrate that H3K27M gliomas show increased protein levels of the SWI/SNF complex ATPase subunits SMARCA4 and SMARCA2, and the PBAF component PBRM1. Additionally, knockdown of mutant H3K27M lowered SMARCA4 protein levels. The proteolysis targeting chimera (PROTAC) AU-15330 that simultaneously targets SMARCA4, SMARCA2, and PBRM1 for degradation exhibits cytotoxicity in H3.3K27M but not H3 wild-type cells. AU-15330 lowered chromatin accessibility measured by ATAC-Seq at nonpromoter regions and reduced global H3K27ac levels. Integrated analysis of gene expression, proteomics, and chromatin accessibility in AU-15330-treated cells demonstrated reduction in the levels of FOXO1, a key member of the forkhead family of transcription factors. Moreover, genetic or pharmacologic targeting of FOXO1 resulted in cell death in H3K27M cells. Overall, our results suggest that H3K27M up-regulates SMARCA4 levels and combined targeting of SWI/SNF ATPases in H3.3K27M can serve as a potent therapeutic strategy for these deadly childhood brain tumors.
    Keywords:  H3K27M mutation; SWI/SNF complex; pediatric brain cancer
    DOI:  https://doi.org/10.1073/pnas.2221175120
  5. Commun Biol. 2023 Apr 22. 6(1): 445
    NF-κB/p52 augments ETS1 binding genome-wide to promote glioma progression.
    Nicholas Sim, Yinghui Li.
      Gliomas are highly invasive and chemoresistant cancers, making them challenging to treat. Chronic inflammation is a key driver of glioma progression as it promotes aberrant activation of inflammatory pathways such as NF-κB signalling, which drives cancer cell invasion and angiogenesis. NF-κB factors typically dimerise with its own family members, but emerging evidence of their promiscuous interactions with other oncogenic factors has been reported to promote transcription of new target genes and function. Here, we show that non-canonical NF-κB activation directly regulates p52 at the ETS1 promoter, activating its expression. This impacts the genomic and transcriptional landscape of ETS1 in a glioma-specific manner. We further show that enhanced non-canonical NF-κB signalling promotes the co-localisation of p52 and ETS1, resulting in transcriptional activation of non-κB and/or non-ETS glioma-promoting genes. We conclude that p52-induced ETS1 overexpression in glioma cells remodels the genome-wide regulatory network of p52 and ETS1 to transcriptionally drive cancer progression.
    DOI:  https://doi.org/10.1038/s42003-023-04821-2
  6. Proc Natl Acad Sci U S A. 2023 May 02. 120(18): e2204621120
    Self-assembling paclitaxel-mediated stimulation of tumor-associated macrophages for postoperative treatment of glioblastoma.
    Feihu Wang, Qian Huang, Hao Su, Mingjiao Sun, Zeyu Wang, Ziqi Chen, Mengzhen Zheng, Rami W Chakroun, Maya K Monroe, Daiqing Chen, Zongyuan Wang, Noah Gorelick, Riccardo Serra, Han Wang, Yun Guan, Jung Soo Suk, Betty Tyler, Henry Brem, Justin Hanes, Honggang Cui.
      The unique cancer-associated immunosuppression in brain, combined with a paucity of infiltrating T cells, contributes to the low response rate and poor treatment outcomes of T cell-based immunotherapy for patients diagnosed with glioblastoma multiforme (GBM). Here, we report on a self-assembling paclitaxel (PTX) filament (PF) hydrogel that stimulates macrophage-mediated immune response for local treatment of recurrent glioblastoma. Our results suggest that aqueous PF solutions containing aCD47 can be directly deposited into the tumor resection cavity, enabling seamless hydrogel filling of the cavity and long-term release of both therapeutics. The PTX PFs elicit an immune-stimulating tumor microenvironment (TME) and thus sensitizes tumor to the aCD47-mediated blockade of the antiphagocytic "don't eat me" signal, which subsequently promotes tumor cell phagocytosis by macrophages and also triggers an antitumor T cell response. As adjuvant therapy after surgery, this aCD47/PF supramolecular hydrogel effectively suppresses primary brain tumor recurrence and prolongs overall survivals with minimal off-target side effects.
    Keywords:  cancer; chemotherapy; hydrogel; immunotherpay; self-assembly
    DOI:  https://doi.org/10.1073/pnas.2204621120
  7. Clin Cancer Res. 2023 Apr 24. pii: CCR-22-2807. [Epub ahead of print]
    Phase II Investigation of TVB-2640 (denifanstat) with Bevacizumab in Patients with First Relapse High-Grade Astrocytoma.
    William Kelly, Adolfo Enrique Diaz Duque, Joel Michalek, Brandon Konkel, Laura Caflisch, Yidong Chen, Sarath Chand Pathuri, Vinu Madhusudanannair Kunnuparampil, John Floyd, Andrew Brenner.
       PURPOSE: Glioblastoma (GBM) represents the most common primary brain tumor. Although anti-angiogenics are employed in the recurrent setting, they do not prolong survival. GBM is known to upregulate fatty acid synthase (FASN) to facilitate lipid biosynthesis. TVB-2640, a FASN inhibitor, impairs this activity.
    PATIENTS AND METHODS: We conducted a prospective, single-center, open-label, unblinded, phase II study of TVB-2640 plus bevacizumab in patients with recurrent high-grade astrocytoma. Patients were randomized to TVB-2640 (100mg/m2 oral daily) plus bevacizumab (10mg/kg IV, D1 and D15) or bevacizumab monotherapy for cycle 1 only (28 days) for biomarker analysis. Thereafter, all patients received TVB-2640 plus bevacizumab until treatment-related toxicity or progressive disease. The primary endpoint was progression-free survival.
    RESULTS: A total of 25 patients were enrolled. The most frequently reported AEs were palmar-plantar erythrodysesthesia, hypertension, mucositis, dry eye, fatigue and skin infection. Most were Grade 1 or 2 in intensity. The ORR for TVB-2640 plus bevacizumab was 56% (CR 17%, PR 39%). PFS6 for TVB-2640 plus bevacizumab was 31.4%. This represented a statistically significant improvement in PFS6 over historical bevacizumab monotherapy (BELOB 16%, p=0.008) and met the primary study endpoint. The observed OS6 was 68%, with survival not reaching significance by log rank test (p=0.56).
    CONCLUSIONS: In this phase II study of relapsed high-grade astrocytoma, TVB-2640 was found to be a well-tolerated oral drug that could be safely combined with bevacizumab. The favorable safety profile and response signals support the initiation of a larger multicenter trial of TVB-2640 plus bevacizumab in astrocytoma.
    DOI:  https://doi.org/10.1158/1078-0432.CCR-22-2807
  8. Sci Adv. 2023 Apr 28. 9(17): eade2675
    The genomic landscape of familial glioma.
    Gliogene Consortium
      Glioma is a rare brain tumor with a poor prognosis. Familial glioma is a subset of glioma with a strong genetic predisposition that accounts for approximately 5% of glioma cases. We performed whole-genome sequencing on an exploratory cohort of 203 individuals from 189 families with a history of familial glioma and an additional validation cohort of 122 individuals from 115 families. We found significant enrichment of rare deleterious variants of seven genes in both cohorts, and the most significantly enriched gene was HERC2 (P = 0.0006). Furthermore, we identified rare noncoding variants in both cohorts that were predicted to affect transcription factor binding sites or cause cryptic splicing. Last, we selected a subset of discovered genes for validation by CRISPR knockdown screening and found that DMBT1, HP1BP3, and ZCH7B3 have profound impacts on proliferation. This study performs comprehensive surveillance of the genomic landscape of familial glioma.
    DOI:  https://doi.org/10.1126/sciadv.ade2675
  9. Neuro Oncol. 2023 Apr 25. pii: noad063. [Epub ahead of print]
    Mitotic index is (still) important for grading IDH-mutant astrocytoma.
    Kaleigh F Roberts, Sonika M Dahiya.
      
    Keywords:  IDH-mutant astrocytoma; grade; mitotic count
    DOI:  https://doi.org/10.1093/neuonc/noad063
  10. bioRxiv. 2023 Apr 13. pii: 2023.04.12.536297. [Epub ahead of print]
    GTP signaling links metabolism, DNA repair, and responses to genotoxic stress.
    Weihua Zhou, Zitong Zhao, Angelica Lin, John Yang, Jie Xu, Wilder-Romans Kari, Annabel Yang, Jing Li, Sumeet Solanki, Jennifer Speth, Natalie Walker, Andrew J Scott, Ayesha U Kothari, Yangyang Yao, Erik R Peterson, Navyateja Korimerla, Christian K Werner, Jessica Liang, Janna Jacobson, Sravya Palavalasa, Alexandra M Obrien, Ameer L Elaimy, Sean P Ferris, Shuang G Zhao, Jann N Sarkaria, Balázs Győrffy, Shuqun Zhang, Wajd N Al-Holou, Yoshie Umemura, Meredith A Morgan, Theodore S Lawrence, Costas A Lyssiotis, Marc Peters-Golden, Yatrik M Shah, Daniel R Wahl.
      How cell metabolism regulates DNA repair is incompletely understood. Here, we define a GTP-mediated signaling cascade that links metabolism to DNA repair and has significant therapeutic implications. GTP, but not other nucleotides, regulates the activity of Rac1, a G protein, that promotes the dephosphorylation of serine 323 on Abl-interactor 1 (Abi-1) by protein phosphatase 5 (PP5). Dephosphorylated Abi-1, a protein previously not known to activate DNA repair, promotes non-homologous end joining. In patients and mouse models of glioblastoma, Rac1 and dephosphorylated Abi-1 mediate DNA repair and resistance to standard of care genotoxic treatments. The GTP-Rac1-PP5-Abi-1 signaling axis is not limited to brain cancer, as GTP supplementation promotes DNA repair and Abi-1-S323 dephosphorylation in non-malignant cells and protects mouse tissues from genotoxic insult. This unexpected ability of GTP to regulate DNA repair independently of deoxynucleotide pools has important implications for normal physiology and cancer treatment.
    DOI:  https://doi.org/10.1101/2023.04.12.536297
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