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  1. Article ; Online: Monocyte-neutrophil entanglement in glioblastoma

    Dinorah Friedmann-Morvinski / Dolores Hambardzumyan

    The Journal of Clinical Investigation, Vol 133, Iss

    2023  Volume 1

    Abstract: Glioblastoma (GBM) is the most belligerent and frequent brain tumor in adults. Research over the past two decades has provided increased knowledge of the genomic and molecular landscape of GBM and highlighted the presence of a high degree of inter- and ... ...

    Abstract Glioblastoma (GBM) is the most belligerent and frequent brain tumor in adults. Research over the past two decades has provided increased knowledge of the genomic and molecular landscape of GBM and highlighted the presence of a high degree of inter- and intratumor heterogeneity within the neoplastic compartment. It is now appreciated that GBMs are composed of multiple distinct and impressionable neoplastic and non-neoplastic cell types that form the unique brain tumor microenvironment (TME). Non-neoplastic cells in the TME form reciprocal interactions with neoplastic cells to promote tumor growth and invasion, and together they influence the tumor response to standard-of-care therapies as well as emerging immunotherapies. One of the most prevalent non-neoplastic cell types in the GBM TME are myeloid cells, the most abundant of which are of hematopoietic origin, including monocytes/monocyte-derived macrophages. Less abundant, although still a notable presence, are neutrophils of hematopoietic origin and intrinsic brain-resident microglia. In this Review we focus on neutrophils and monocytes that infiltrate tumors from the blood circulation, their heterogeneity, and their interactions with neoplastic cells and other non-neoplastic cells in the TME. We conclude with an overview of challenges in targeting these cells and discuss avenues for therapeutic exploitation to improve the dismal outcomes of patients with GBM.
    Keywords Medicine ; R
    Subject code 610
    Language English
    Publishing date 2023-01-01T00:00:00Z
    Publisher American Society for Clinical Investigation
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  2. Article ; Online: Current knowledge on the immune microenvironment and emerging immunotherapies in diffuse midline glioma

    Gabrielle Price / Alexandros Bouras / Dolores Hambardzumyan / Constantinos G. Hadjipanayis

    EBioMedicine, Vol 69, Iss , Pp 103453- (2021)

    2021  

    Abstract: Diffuse midline glioma (DMG) is an incurable malignancy with the highest mortality rate among pediatric brain tumors. While radiotherapy and chemotherapy are the most common treatments, these modalities have limited promise. Due to their diffuse nature ... ...

    Abstract Diffuse midline glioma (DMG) is an incurable malignancy with the highest mortality rate among pediatric brain tumors. While radiotherapy and chemotherapy are the most common treatments, these modalities have limited promise. Due to their diffuse nature in critical areas of the brain, the prognosis of DMG remains dismal. DMGs are characterized by unique phenotypic heterogeneity and histological features. Mutations of H3K27M, TP53, and ACVR1 drive DMG tumorigenesis. Histological artifacts include pseudopalisading necrosis and vascular endothelial proliferation. Mouse models that recapitulate human DMG have been used to study key driver mutations and the tumor microenvironment. DMG consists of a largely immunologically cold tumor microenvironment that lacks immune cell infiltration, immunosuppressive factors, and immune surveillance. While tumor-associated macrophages are the most abundant immune cell population, there is reduced T lymphocyte infiltration. Immunotherapies can stimulate the immune system to find, attack, and eliminate cancer cells. However, it is critical to understand the immune microenvironment of DMG before designing immunotherapies since differences in the microenvironment influence treatment efficacy. To this end, our review aims to overview the immune microenvironment of DMG, discuss emerging insights about the immune landscape that drives disease pathophysiology, and present recent findings and new opportunities for therapeutic discovery.
    Keywords Diffuse midline glioma ; Microenvironment ; Macrophage ; Microglia ; Immunotherapy ; H3K27M ; Medicine ; R ; Medicine (General) ; R5-920
    Subject code 616
    Language English
    Publishing date 2021-07-01T00:00:00Z
    Publisher Elsevier
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  3. Article ; Online: Integrin α3β1 promotes vessel formation of glioblastoma-associated endothelial cells through calcium-mediated macropinocytosis and lysosomal exocytosis

    Eunnyung Bae / Ping Huang / Gaёlle Müller-Greven / Dolores Hambardzumyan / Andrew Edward Sloan / Amy S. Nowacki / Nicholas Marko / Cathleen R. Carlin / Candece L. Gladson

    Nature Communications, Vol 13, Iss 1, Pp 1-

    2022  Volume 15

    Abstract: Tumour-associated angiogenesis facilitates the growth of tumours. Here the authors show that integrin α3β1 promotes blood vessel formation in glioblastoma through calcium-mediated macropinocytosis and lysosomal exocytosis. ...

    Abstract Tumour-associated angiogenesis facilitates the growth of tumours. Here the authors show that integrin α3β1 promotes blood vessel formation in glioblastoma through calcium-mediated macropinocytosis and lysosomal exocytosis.
    Keywords Science ; Q
    Language English
    Publishing date 2022-07-01T00:00:00Z
    Publisher Nature Portfolio
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  4. Article ; Online: Monocyte depletion enhances neutrophil influx and proneural to mesenchymal transition in glioblastoma

    Zhihong Chen / Nishant Soni / Gonzalo Pinero / Bruno Giotti / Devon J. Eddins / Katherine E. Lindblad / James L. Ross / Montserrat Puigdelloses Vallcorba / Tanvi Joshi / Angelo Angione / Wes Thomason / Aislinn Keane / Nadejda M. Tsankova / David H. Gutmann / Sergio A. Lira / Amaia Lujambio / Eliver E. B. Ghosn / Alexander M. Tsankov / Dolores Hambardzumyan

    Nature Communications, Vol 14, Iss 1, Pp 1-

    2023  Volume 24

    Abstract: Myeloid cells are the predominant cell type in the tumor microenvironment of human and murine glioblastoma (GBM). By generating a mouse model deficient for all monocyte chemoattractant proteins, here the authors show that blocking monocyte recruitment ... ...

    Abstract Myeloid cells are the predominant cell type in the tumor microenvironment of human and murine glioblastoma (GBM). By generating a mouse model deficient for all monocyte chemoattractant proteins, here the authors show that blocking monocyte recruitment promotes a compensatory neutrophil influx and that concomitant neutrophil inhibition is required to improve survival in GBM preclinical models.
    Keywords Science ; Q
    Language English
    Publishing date 2023-04-01T00:00:00Z
    Publisher Nature Portfolio
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  5. Article ; Online: Comprehensive Protein Interactome Analysis of a Key RNA Helicase

    Rebecca Bish / Nerea Cuevas-Polo / Zhe Cheng / Dolores Hambardzumyan / Mathias Munschauer / Markus Landthaler / Christine Vogel

    Biomolecules, Vol 5, Iss 3, Pp 1441-

    Detection of Novel Stress Granule Proteins

    2015  Volume 1466

    Abstract: DDX6 (p54/RCK) is a human RNA helicase with central roles in mRNA decay and translation repression. To help our understanding of how DDX6 performs these multiple functions, we conducted the first unbiased, large-scale study to map the DDX6-centric ... ...

    Abstract DDX6 (p54/RCK) is a human RNA helicase with central roles in mRNA decay and translation repression. To help our understanding of how DDX6 performs these multiple functions, we conducted the first unbiased, large-scale study to map the DDX6-centric protein-protein interactome using immunoprecipitation and mass spectrometry. Using DDX6 as bait, we identify a high-confidence and high-quality set of protein interaction partners which are enriched for functions in RNA metabolism and ribosomal proteins. The screen is highly specific, maximizing the number of true positives, as demonstrated by the validation of 81% (47/58) of the RNA-independent interactors through known functions and interactions. Importantly, we minimize the number of indirect interaction partners through use of a nuclease-based digestion to eliminate RNA. We describe eleven new interactors, including proteins involved in splicing which is an as-yet unknown role for DDX6. We validated and characterized in more detail the interaction of DDX6 with Nuclear fragile X mental retardation-interacting protein 2 (NUFIP2) and with two previously uncharacterized proteins, FAM195A and FAM195B (here referred to as granulin-1 and granulin-2, or GRAN1 and GRAN2). We show that NUFIP2, GRAN1, and GRAN2 are not P-body components, but re-localize to stress granules upon exposure to stress, suggesting a function in translation repression in the cellular stress response. Using a complementary analysis that resolved DDX6’s multiple complex memberships, we further validated these interaction partners and the presence of splicing factors. As DDX6 also interacts with the E3 SUMO ligase TIF1β, we tested for and observed a significant enrichment of sumoylation amongst DDX6’s interaction partners. Our results represent the most comprehensive screen for direct interaction partners of a key regulator of RNA life cycle and localization, highlighting new stress granule components and possible DDX6 functions—many of which are likely conserved across eukaryotes.
    Keywords DDX6 ; post-transcriptional regulation ; protein interactions ; SUMOylation ; NUFIP2 ; FAM195A ; FAM195B ; stress granules ; P bodies ; mRNA degradation ; Biology (General) ; QH301-705.5 ; Science ; Q
    Subject code 580
    Language English
    Publishing date 2015-07-01T00:00:00Z
    Publisher MDPI AG
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  6. Article ; Online: Comprehensive Protein Interactome Analysis of a Key RNA Helicase

    Rebecca Bish / Nerea Cuevas-Polo / Zhe Cheng / Dolores Hambardzumyan / Mathias Munschauer / Markus Landthaler / Christine Vogel

    Biomolecules, Vol 5, Iss 3, Pp 1441-

    Detection of Novel Stress Granule Proteins

    2015  Volume 1466

    Abstract: DDX6 (p54/RCK) is a human RNA helicase with central roles in mRNA decay and translation repression. To help our understanding of how DDX6 performs these multiple functions, we conducted the first unbiased, large-scale study to map the DDX6-centric ... ...

    Abstract DDX6 (p54/RCK) is a human RNA helicase with central roles in mRNA decay and translation repression. To help our understanding of how DDX6 performs these multiple functions, we conducted the first unbiased, large-scale study to map the DDX6-centric protein-protein interactome using immunoprecipitation and mass spectrometry. Using DDX6 as bait, we identify a high-confidence and high-quality set of protein interaction partners which are enriched for functions in RNA metabolism and ribosomal proteins. The screen is highly specific, maximizing the number of true positives, as demonstrated by the validation of 81% (47/58) of the RNA-independent interactors through known functions and interactions. Importantly, we minimize the number of indirect interaction partners through use of a nuclease-based digestion to eliminate RNA. We describe eleven new interactors, including proteins involved in splicing which is an as-yet unknown role for DDX6. We validated and characterized in more detail the interaction of DDX6 with Nuclear fragile X mental retardation-interacting protein 2 (NUFIP2) and with two previously uncharacterized proteins, FAM195A and FAM195B (here referred to as granulin-1 and granulin-2, or GRAN1 and GRAN2). We show that NUFIP2, GRAN1, and GRAN2 are not P-body components, but re-localize to stress granules upon exposure to stress, suggesting a function in translation repression in the cellular stress response. Using a complementary analysis that resolved DDX6’s multiple complex memberships, we further validated these interaction partners and the presence of splicing factors. As DDX6 also interacts with the E3 SUMO ligase TIF1β, we tested for and observed a significant enrichment of sumoylation amongst DDX6’s interaction partners. Our results represent the most comprehensive screen for direct interaction partners of a key regulator of RNA life cycle and localization, highlighting new stress granule components and possible DDX6 functions—many of which are likely conserved across eukaryotes.
    Keywords DDX6 ; post-transcriptional regulation ; protein interactions ; SUMOylation ; NUFIP2 ; FAM195A ; FAM195B ; stress granules ; P bodies ; mRNA degradation ; Biology (General) ; QH301-705.5 ; Science ; Q
    Subject code 580
    Language English
    Publishing date 2015-07-01T00:00:00Z
    Publisher MDPI AG
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  7. Article ; Online: Comprehensive Protein Interactome Analysis of a Key RNA Helicase

    Rebecca Bish / Nerea Cuevas-Polo / Zhe Cheng / Dolores Hambardzumyan / Mathias Munschauer / Markus Landthaler / Christine Vogel

    Biomolecules, Vol 5, Iss 3, Pp 1441-

    Detection of Novel Stress Granule Proteins

    2015  Volume 1466

    Abstract: DDX6 (p54/RCK) is a human RNA helicase with central roles in mRNA decay and translation repression. To help our understanding of how DDX6 performs these multiple functions, we conducted the first unbiased, large-scale study to map the DDX6-centric ... ...

    Abstract DDX6 (p54/RCK) is a human RNA helicase with central roles in mRNA decay and translation repression. To help our understanding of how DDX6 performs these multiple functions, we conducted the first unbiased, large-scale study to map the DDX6-centric protein-protein interactome using immunoprecipitation and mass spectrometry. Using DDX6 as bait, we identify a high-confidence and high-quality set of protein interaction partners which are enriched for functions in RNA metabolism and ribosomal proteins. The screen is highly specific, maximizing the number of true positives, as demonstrated by the validation of 81% (47/58) of the RNA-independent interactors through known functions and interactions. Importantly, we minimize the number of indirect interaction partners through use of a nuclease-based digestion to eliminate RNA. We describe eleven new interactors, including proteins involved in splicing which is an as-yet unknown role for DDX6. We validated and characterized in more detail the interaction of DDX6 with Nuclear fragile X mental retardation-interacting protein 2 (NUFIP2) and with two previously uncharacterized proteins, FAM195A and FAM195B (here referred to as granulin-1 and granulin-2, or GRAN1 and GRAN2). We show that NUFIP2, GRAN1, and GRAN2 are not P-body components, but re-localize to stress granules upon exposure to stress, suggesting a function in translation repression in the cellular stress response. Using a complementary analysis that resolved DDX6’s multiple complex memberships, we further validated these interaction partners and the presence of splicing factors. As DDX6 also interacts with the E3 SUMO ligase TIF1β, we tested for and observed a significant enrichment of sumoylation amongst DDX6’s interaction partners. Our results represent the most comprehensive screen for direct interaction partners of a key regulator of RNA life cycle and localization, highlighting new stress granule components and possible DDX6 functions—many of which are likely conserved across eukaryotes.
    Keywords DDX6 ; post-transcriptional regulation ; protein interactions ; SUMOylation ; NUFIP2 ; FAM195A ; FAM195B ; stress granules ; P bodies ; mRNA degradation ; Biology (General) ; QH301-705.5 ; Science ; Q
    Subject code 580
    Language English
    Publishing date 2015-07-01T00:00:00Z
    Publisher MDPI AG
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  8. Article ; Online: Tumour-associated macrophages exhibit anti-tumoural properties in Sonic Hedgehog medulloblastoma

    Victor Maximov / Zhihong Chen / Yun Wei / M. Hope Robinson / Cameron J. Herting / Nithya S. Shanmugam / Vasilisa A. Rudneva / Kelly C. Goldsmith / Tobey J. MacDonald / Paul A. Northcott / Dolores Hambardzumyan / Anna M. Kenney

    Nature Communications, Vol 10, Iss 1, Pp 1-

    2019  Volume 11

    Abstract: The Sonic Hedgehog subgroup of medulloblastoma are characterised by the high infiltration of tumour-associated macrophages (TAMs). Here, the authors show that TAM numbers in patients are associated with better prognosis and that, consistently, in a ... ...

    Abstract The Sonic Hedgehog subgroup of medulloblastoma are characterised by the high infiltration of tumour-associated macrophages (TAMs). Here, the authors show that TAM numbers in patients are associated with better prognosis and that, consistently, in a murine model of medulloblastoma, these TAMs have anti-tumoural properties.
    Keywords Science ; Q
    Language English
    Publishing date 2019-06-01T00:00:00Z
    Publisher Nature Publishing Group
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  9. Article ; Online: Tumour-associated macrophages exhibit anti-tumoural properties in Sonic Hedgehog medulloblastoma

    Victor Maximov / Zhihong Chen / Yun Wei / M. Hope Robinson / Cameron J. Herting / Nithya S. Shanmugam / Vasilisa A. Rudneva / Kelly C. Goldsmith / Tobey J. MacDonald / Paul A. Northcott / Dolores Hambardzumyan / Anna M. Kenney

    Nature Communications, Vol 10, Iss 1, Pp 1-

    2019  Volume 11

    Abstract: The Sonic Hedgehog subgroup of medulloblastoma are characterised by the high infiltration of tumour-associated macrophages (TAMs). Here, the authors show that TAM numbers in patients are associated with better prognosis and that, consistently, in a ... ...

    Abstract The Sonic Hedgehog subgroup of medulloblastoma are characterised by the high infiltration of tumour-associated macrophages (TAMs). Here, the authors show that TAM numbers in patients are associated with better prognosis and that, consistently, in a murine model of medulloblastoma, these TAMs have anti-tumoural properties.
    Keywords Science ; Q
    Language English
    Publishing date 2019-06-01T00:00:00Z
    Publisher Nature Portfolio
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  10. Article ; Online: The probable cell of origin of NF1- and PDGF-driven glioblastomas.

    Dolores Hambardzumyan / Yu-Kang Cheng / Hiroshi Haeno / Eric C Holland / Franziska Michor

    PLoS ONE, Vol 6, Iss 9, p e

    2011  Volume 24454

    Abstract: Primary glioblastomas are subdivided into several molecular subtypes. There is an ongoing debate over the cell of origin for these tumor types where some suggest a progenitor while others argue for a stem cell origin. Even within the same molecular ... ...

    Abstract Primary glioblastomas are subdivided into several molecular subtypes. There is an ongoing debate over the cell of origin for these tumor types where some suggest a progenitor while others argue for a stem cell origin. Even within the same molecular subgroup, and using lineage tracing in mouse models, different groups have reached different conclusions. We addressed this problem from a combined mathematical modeling and experimental standpoint. We designed a novel mathematical framework to identify the most likely cells of origin of two glioma subtypes. Our mathematical model of the unperturbed in vivo system predicts that if a genetic event contributing to tumor initiation imparts symmetric self-renewing cell division (such as PDGF overexpression), then the cell of origin is a transit amplifier. Otherwise, the initiating mutations arise in stem cells. The mathematical framework was validated with the RCAS/tv-a system of somatic gene transfer in mice. We demonstrated that PDGF-induced gliomas can be derived from GFAP-expressing cells of the subventricular zone or the cortex (reactive astrocytes), thus validating the predictions of our mathematical model. This interdisciplinary approach allowed us to determine the likelihood that individual cell types serve as the cells of origin of gliomas in an unperturbed system.
    Keywords Medicine ; R ; Science ; Q
    Subject code 190
    Language English
    Publishing date 2011-01-01T00:00:00Z
    Publisher Public Library of Science (PLoS)
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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