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  • 1
    Online Resource
    Online Resource
    TMET-09. LOSS OF MAT2A COMPROMISES METHIONINE METABOLISM AND REPRESENTS A VULNERABILITY IN H3K27M MUTANT GLIOMAS
    Oxford University Press (OUP) ; 2022
    In:  Neuro-Oncology Vol. 24, No. Supplement_7 ( 2022-11-14), p. vii263-vii263
    Details
    In: Neuro-Oncology, Oxford University Press (OUP), Vol. 24, No. Supplement_7 ( 2022-11-14), p. vii263-vii263
    Abstract: H3K27-mutant diffuse midline gliomas (DMGs) are defined as grade IV tumors by the World Health Organization. DMGs are inoperable and resistant to chemo/radio therapies. Median survival ranges from 8-11 months, with 2% of patients surviving beyond 5 years. H3K27M mutations lead to global epigenetic and transcriptional reprogramming driven by global loss of negative transcriptional regulator H3K27 trimethylation (H3K27me3). Loss of H3K27me3 is an initiating event in gliomagenesis. This disease lacks appropriate models to predict disease biology and response to treatment. Therefore, we developed a novel syngeneic H3K27M mouse model. An unbiased integrated systems biology approach identified that H3K27M but not isogenic controls relied on the amino acid methionine and the enzyme Methionine Adenosyltransferase 2A (MAT2A). MAT2A is a central regulator of one-carbon metabolism by converting methionine to S-adenosylmethionine (SAM), the universal methyl-donor for protein and nucleotide methylation reactions. In complementary genetic approaches, we applied these findings to patient-derived cell lines with the H3K27M mutation. We hypothesize that MAT2A abrogation, genetic/pharmacological, would alter DMG viability by disrupting the methylome. The current MAT2A sensitivity paradigm is based on Methylthioadenosine Phosphorylase (MTAP) deletion through a synthetic lethal mechanism. We provide a novel mechanism whereby H3K27M cells are sensitive to MAT2A loss, independent of MTAP and through Adenosylmethionine Decarboxylase 1 (AMD1) overexpression disrupting MAT2A regulation. This results in H3K27M cells having lower MAT2A protein levels, conferring a sensitivity by inhibiting residual MAT2A. Genetic/pharmacological aberrations to MAT2A resulted in reduced proliferation. Parallel H3K36me3 ChIP and RNA-sequencing identified loss of oncogenic and developmental transcriptional programs associated with MAT2A loss. In vivo syngeneic and patient-derived xenograft models with both inducible MAT2A knockdown or methionine restricted diets showed extended survival. These results suggest novel interactions between methionine metabolism and the epigenome of H3K27M gliomas and provide evidence that MAT2A, presents exploitable therapeutic vulnerabilities in histone mutant gliomas.
    Type of Medium: Online Resource
    ISSN: 1522-8517 , 1523-5866
    URL: Article
    DOI: 10.1093/neuonc/noac209.1014
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2022
    detail.hit.zdb_id: 2094060-9
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  • 2
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    Online Resource
    OTME-20. Chitinase-3-like-1(CHI3L1) Protein Complexes Regulate the immunosuppressive Microenvironment in Glioblastoma
    Oxford University Press (OUP) ; 2021
    In:  Neuro-Oncology Advances Vol. 3, No. Supplement_2 ( 2021-07-05), p. ii17-ii18
    Details
    In: Neuro-Oncology Advances, Oxford University Press (OUP), Vol. 3, No. Supplement_2 ( 2021-07-05), p. ii17-ii18
    Abstract: Glioblastoma (GBM) is the most common and highly malignant brain tumor in adults. Despite advances in multimodal treatment, GBM remains largely incurable. While immunotherapies have been highly effective in some types of cancer, the disappointing results from clinical trials for GBM immunotherapy represent continued challenges. GBM is highly immunosuppressive and resistant to immunotherapy because of glioma cells escaping from immune surveillance by reprograming the tumor microenvironment (TME). However, understanding the mechanisms of immune evasion by GBM remains elusive. Based on unbiased approaches, we found that Chitinase-3-like-1 (CHI3L1), also known as human homolog YKL-40, is highly expressed in GBM, which is regulated by the CHI3L1-PI3K/AKT/mTOR signaling in a positive feedback loop. Gain- and loss-function studies reveal that CHI3L1 plays a predominant role in regulating an immunosuppressive microenvironment by reprogramming tumor-associated macrophages (TAMs). Using the liquid chromatography-mass spectrometry and orthogonal structure-based screening, we found that Galectin-3 binding protein (Gal3BP) and its binding partner, Galectin-3 (Gal3), can interact competitively with the same binding motif on CHI3L1, leading to selective migration of M2-like versus M1-like bone marrow-derived macrophages (BMDMs) and resident microglia (MG). Mechanistically, the CHI3L1-Gal3 protein complex governs a transcriptional program of NFκB/CEBPβ to control the protumor phenotype of BMDMs, leading to inhibition of T cell infiltration and activation in the GBM TME. However, Gal3BP can reverse CHI3L1-Gal3 induced signaling pathway activation and subsequent protumor phenotype in TAMs. Based on protein binding motifs, a newly developed Gal3BP mimetic peptide can attenuate immune suppression and tumor progression in the syngeneic GBM mouse models, including decreasing M2-like TAMs and increasing M1-like TAMs and T cell infiltration. Together, these results shed light on the role of CHI3L1 protein complexes in immune evasion by glioblastoma and as a potential immunotherapeutic target for this devastating disease.
    Type of Medium: Online Resource
    ISSN: 2632-2498
    URL: Article
    DOI: 10.1093/noajnl/vdab070.071
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2021
    detail.hit.zdb_id: 3009682-0
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  • 3
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    Online Resource
    Development of a human glioblastoma model using humanized DRAG mice for immunotherapy
    Oxford University Press (OUP) ; 2023
    In:  Antibody Therapeutics
    Details
    In: Antibody Therapeutics, Oxford University Press (OUP)
    Abstract: Glioblastoma (GBM) is the most common and lethal primary brain tumor, with high mortality rates and a short median survival rate of about 15 months despite intensive multimodal treatment of maximal surgical resection, radiotherapy, and chemotherapy. Although immunotherapies have been successful in treating various cancers, disappointing results from clinical trials for GBM immunotherapy represent our incomplete understanding. The development of alternative humanized mouse models with fully functional human immune cells will potentially accelerate the progress of GBM immunotherapy. Methods The humanized DRAG mice were generated by γ-irradiation following tail vein injection of human DR4+ hematopoietic stem cells (hHSCs). The humanization was confirmed by immunostaining and flow cytometry after three months of hHSC injection. The GBM patient-derived tumorsphere cells, TS543 and GSC262, were intracranially injected in these DRAG mice to form xenografted tumors. The GBM tumors were characterized by the pathological features and the immune cell composition using immunohistochemistry staining and microscopy, as well as flow cytometry. In addition, the mice were intravenously administrated with anti-PD-1 antibody and followed by characterization of tumor-infiltrating immunosuppressive cell populations. Results In this study, we developed a humanized DRAG (NOD.Rag1KO.IL2RγcKO) mouse model, in which the human hematopoietic stem cells (HSCs) were well-engrafted and subsequently differentiated into a full lineage of immune cells. Using this humanized DRAG mouse model, GBM patient-derived tumorsphere lines were successfully engrafted to form xenografted tumors, which can recapitulate the pathological features and the immune cell composition of human GBM. Importantly, the administration of anti-human PD-1 antibodies in these DRAG mice bearing a GBM patient-derived tumorsphere line resulted in decreasing the major tumor-infiltrating immunosuppressive cell populations, including CD4+PD-1+ and CD8+PD-1+ T cells, CD11b+CD14+HLA-DR+ macrophages, CD11b+CD14+HLA-DR−CD15− and CD11b+CD14−CD15+ myeloid-derived suppressor cells, indicating the humanized DRAG mouse model as a useful model to test the efficacy of immune checkpoint inhibitors and CAR T-cell treatment in GBM immunotherapy. Conclusions Taken together, these results suggest that humanized DRAG mouse model is a reliable preclinical platform for studying brain cancer immunotherapy and beyond.
    Type of Medium: Online Resource
    ISSN: 2516-4236
    URL: Article
    DOI: 10.1093/abt/tbad021
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2023
    detail.hit.zdb_id: 3031893-2
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  • 4
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    Online Resource
    Role of Mediator in Regulating Pol II Elongation and Nucleosome Displacement in Saccharomyces cerevisiae
    Oxford University Press (OUP) ; 2012
    In:  Genetics Vol. 191, No. 1 ( 2012-05-01), p. 95-106
    Details
    In: Genetics, Oxford University Press (OUP), Vol. 191, No. 1 ( 2012-05-01), p. 95-106
    Abstract: Mediator is a modular multisubunit complex that functions as a critical coregulator of RNA polymerase II (Pol II) transcription. While it is well accepted that Mediator plays important roles in the assembly and function of the preinitiation complex (PIC), less is known of its potential roles in regulating downstream steps of the transcription cycle. Here we use a combination of genetic and molecular approaches to investigate Mediator regulation of Pol II elongation in the model eukaryote, Saccharomyces cerevisiae. We find that ewe (expressionwithout heat shockelement) mutations in conserved Mediator subunits Med7, Med14, Med19, and Med21—all located within or adjacent to the middle module—severely diminish heat-shock–induced expression of the Hsf1-regulated HSP82 gene. Interestingly, these mutations do not impede Pol II recruitment to the gene’s promoter but instead impair its transit through the coding region. This implies that a normal function of Mediator is to regulate a postinitiation step at HSP82. In addition, displacement of histones from promoter and coding regions, a hallmark of activated heat-shock genes, is significantly impaired in the med14 and med21 mutants. Suggestive of a more general role, ewe mutations confer hypersensitivity to the anti-elongation drug 6-azauracil (6-AU) and one of them—med21—impairs Pol II processivity on a GAL1-regulated reporter gene. Taken together, our results suggest that yeast Mediator, acting principally through its middle module, can regulate Pol II elongation at both heat-shock and non–heat-shock genes.
    Type of Medium: Online Resource
    ISSN: 1943-2631
    URL: Article
    DOI: 10.1534/genetics.111.135806
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2012
    detail.hit.zdb_id: 1477228-0
    SSG: 12
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  • 5
    Online Resource
    Online Resource
    TAMI-50. CHITINASE-3-LIKE-1 PROTEIN BINDING COMPLEXES REGULATE IMMUNE SUPPRESSION IN GLIOBLASTOMA
    Oxford University Press (OUP) ; 2020
    In:  Neuro-Oncology Vol. 22, No. Supplement_2 ( 2020-11-09), p. ii224-ii224
    Details
    In: Neuro-Oncology, Oxford University Press (OUP), Vol. 22, No. Supplement_2 ( 2020-11-09), p. ii224-ii224
    Abstract: Glioblastoma (GBM), the most common and lethal brain tumor, remains incurable despite intensive multimodal treatment. While immunotherapies have been highly effective in some types of cancer, the disappointing results from clinical trials for GBM immunotherapy represent continued challenges. GBM is highly immunosuppressive and resistant to immunotherapy because of glioma cells escaping from immune surveillance by reprograming the tumor microenvironment (TME). However, understanding the mechanisms of immune evasion by GBM remains elusive. Here, we found that Chitinase-3-like-1 (CHI3L1) is highly expressed in GBM and associated with a poor clinical outcome. CHI3L1, also known as human homolog YKL-40, plays a role in tissue remodeling, inflammation and cancer. Interestingly, we found that genetic knockdown (KD) of Chi3l1 in syngeneic immunocompetent mouse GBM models resulted in increased tumor-infiltrating lymphocytes, tumor size reduction, and improved animal survival. Surprisingly, the parallel loss-of-function experiment revealed that Chi3l1 KD did not repress tumor progression in the orthotopic immunodeficient mice with deficient T and B cells. These results suggest the predominant role of CHI3L1 in regulating the GBM immune TME, rather than in tumor cells per se. Mechanistically, we discovered that Galectin-3 (Gal-3) and Galectin-3 binding protein (Gal-3BP) interact competitively with the same binding motif on CHI3L1, leading to selective migration of protumor M2-like versus antitumor M1-like bone marrow-derived macrophages (BMDMs) and resident microglia (MG). Transcriptomic analysis revealed that pro-inflammatory signature and T cell mediated immunity and cytotoxicity signaling are significantly enriched in tumor associated macrophages/microglia (TAMs) composed of BMDMs and MG, which were isolated from tumors with Chi3l1 KD versus wild type. In vitro validations suggest that CHI3L1-Gal-3, but not CHI3L1-Gal-3BP protein binding complex, activates PI3K/AKT/mTOR signaling to control the TAM switch of immune suppression and immune stimulation. Together, these results shed light on molecular mechanism of GBM immune evasion and potential new immunotherapeutic strategies for GBM treatment.
    Type of Medium: Online Resource
    ISSN: 1522-8517 , 1523-5866
    URL: Article
    DOI: 10.1093/neuonc/noaa215.937
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2020
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  • 6
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    Online Resource
    TMIC-49. CHITINASE-3-LIKE 1 PROTEIN COMPLEXES REGULATE PD-1 SIGNALING-MEDIATED IMMUNOSUPPRESSION IN GLIOBLASTOMA
    Oxford University Press (OUP) ; 2022
    In:  Neuro-Oncology Vol. 24, No. Supplement_7 ( 2022-11-14), p. vii282-vii282
    Details
    In: Neuro-Oncology, Oxford University Press (OUP), Vol. 24, No. Supplement_7 ( 2022-11-14), p. vii282-vii282
    Abstract: Glioblastoma (GBM), the most common and lethal brain tumor with a median survival rate of only 15 months, remains largely incurable despite intensive multimodal treatment, including immunotherapeutic strategies being tested in clinical trials. GBM is highly immunosuppressive and resistant to immunotherapy because glioma cells escape from effective antitumor immunity through programing the tumor microenvironment (TME). Owing to the tremendous heterogeneity and plasticity of tumor cells and the surrounding TME, understanding the mechanisms of immune evasion by GBM remains elusive. We have recently discovered that the Chitinase-3-like-1 (CHI3L1)-Galectin-3 (Gal3) protein binding complex can selectively promote tumor-associated macrophage migration and infiltration with a protumor M2-like phenotype and T cell-mediated immunosuppression, which are governed by a transcriptional program of NF-κB/CEBPβ in the CHI3L1/Gal3-PI3K/AKT/mTOR axis. The immunoprecipitation coupled to liquid chromatography-mass spectrometry analysis revealed that galectin 3–binding protein (Gal3BP) competes with Gal3 to bind with CHI3L1 for negative regulation of the CHI3L1-Gal3 mediated processes. Interestingly, a newly-developed Gal3BP mimetic peptide can disrupt CHI3L1-Gal3 interaction, resulting in decreasing migration of M2-like bone marrow-derived macrophages (BMDMs), increasing CD8+ T cell infiltration, reversing immunosuppression, and inhibiting tumor progression in vitro and in vivo. Analyzing PD-1 signaling activation, we found that the Gal3BP mimetic peptide significantly decreased PD-L1 expression in tumor cells. Correlation analysis showed that CHI31L and Gal3 (encoded by LGALS3 gene) are significantly associated with both PD-L1 and PD-L2 in GBM patient samples. Furthermore, overexpression of CHI3L1 increased expression levels of PD-L1 and PD-L2, and CHI3L1 deletion decreased their expression in GBM patient-derived neurosphere lines. The treatment with recombinant CHI3L1 protein significantly increased PD-L1 and PD-L2 expression in M2-like BMDMs (with high levels of endogenous Gal3). Collectively, these data suggest that CHI3L1 protein complexes control the GBM immunosuppressive microenvironment by PD-1/PD-L1/PD-L2 signaling, providing new immunotherapeutic strategies for this brain cancer.
    Type of Medium: Online Resource
    ISSN: 1522-8517 , 1523-5866
    URL: Article
    DOI: 10.1093/neuonc/noac209.1093
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2022
    detail.hit.zdb_id: 2094060-9
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  • 7
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    Online Resource
    TMIC-14. AUTO-/PARACRINE SIGNALING OF PI3K/AKT/YKL-40 IN MESENCHYMAL GLIOBLASTOMA PROGRESSION
    Oxford University Press (OUP) ; 2018
    In:  Neuro-Oncology Vol. 20, No. suppl_6 ( 2018-11-05), p. vi258-vi259
    Details
    In: Neuro-Oncology, Oxford University Press (OUP), Vol. 20, No. suppl_6 ( 2018-11-05), p. vi258-vi259
    Type of Medium: Online Resource
    ISSN: 1522-8517 , 1523-5866
    URL: Article
    DOI: 10.1093/neuonc/noy148.1073
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2018
    detail.hit.zdb_id: 2094060-9
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