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  • 1
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    Online Resource
    Betacellulin drives therapy resistance in glioblastoma
    Oxford University Press (OUP) ; 2020
    In:  Neuro-Oncology Vol. 22, No. 4 ( 2020-04-15), p. 457-469
    Details
    In: Neuro-Oncology, Oxford University Press (OUP), Vol. 22, No. 4 ( 2020-04-15), p. 457-469
    Abstract: The transcription factor signal transducer and activator of transcription 3 (STAT3) drives progression in glioblastoma (GBM), suggesting STAT3 as a therapeutic target. Surprisingly however, GBM cells generally show primary resistance to STAT3 blockade. Methods Human glioblastoma cell lines LN229, U87, SF767, and U373, and patient-derived xenografts (PDXs) GBM8 and GBM43 were used to evaluate epidermal growth factor receptor (EGFR) activation during STAT3 inhibition. Protein and gene expression experiments, protein stability assays, cytokine arrays, phospho-tyrosine arrays and EGFR-ligand protein arrays were performed on STAT3 inhibitor–treated cells. To evaluate antitumor activity, we administered a betacellulin (BTC)-neutralizing antibody alone and in combination with STAT3 inhibition. BTC is an EGFR ligand. We therefore treated mice with orthotopic xenografts using the third-generation EGFR inhibitor osimertinib, with or without STAT3 knockdown. Results We demonstrate that both small-molecule inhibitors and knockdown of STAT3 led to expression and secretion of the EGFR ligand BTC, resulting in activation of EGFR and subsequent downstream phosphorylation of nuclear factor-kappaB (NF-κB). Neutralizing antibody against BTC abrogated activation of both EGFR and NF-κB in response to inhibition of STAT3; with combinatorial blockade of STAT3 and BTC inducing apoptosis in GBM cells. Blocking EGFR and STAT3 together inhibited tumor growth, improving survival in mice bearing orthotopic GBM PDXs in vivo. Conclusion These data reveal a feedback loop among STAT3, EGFR, and NF-κB that mediates primary resistance to STAT3 blockade and suggest strategies for therapeutic intervention.
    Type of Medium: Online Resource
    ISSN: 1522-8517 , 1523-5866
    URL: Article
    DOI: 10.1093/neuonc/noz206
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2020
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  • 2
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    Therapy-Induced Evolution of Human Lung Cancer Revealed by Single-Cell RNA Sequencing
    Elsevier BV ; 2020
    In:  Cell Vol. 182, No. 5 ( 2020-09), p. 1232-1251.e22
    Details
    In: Cell, Elsevier BV, Vol. 182, No. 5 ( 2020-09), p. 1232-1251.e22
    Type of Medium: Online Resource
    ISSN: 0092-8674
    URL: Article
    DOI: 10.1016/j.cell.2020.07.017
    RVK:
    XA 36269
    RVK:
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    Language: English
    Publisher: Elsevier BV
    Publication Date: 2020
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  • 3
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    Chronic Lymphocytic Leukemia-Derived Extracellular Vesicles Contain a Distinctive Proteome, As Well As Specific Micro RNAs and Y RNAs
    American Society of Hematology ; 2014
    In:  Blood Vol. 124, No. 21 ( 2014-12-06), p. 1968-1968
    Details
    In: Blood, American Society of Hematology, Vol. 124, No. 21 ( 2014-12-06), p. 1968-1968
    Abstract: The pathogenesis of chronic lymphocytic leukemia (CLL) is stringently associated with a tumor-supportive microenvironment and a dysfunctional immune system. Of note, CLL cells themselves induce changes in surrounding cells, and extracellular vesicles (EVs) released by CLL cells represent a newly discovered mechanism of cell-cell communication. EVs are membrane enclosed nanoparticles 30 to 1000 nm in size and are able to reprogram recipient cells by transferring proteins and RNA molecules from their cell of origin. Thus, we aimed to analyze CLL cell-derived EVs present in blood plasma of CLL patients as well as those released by the CLL cell line MEC-1, in order to understand their role within the microenvironment. EVs were isolated from blood plasma of CLL patients and healthy donors, as well as from MEC-1 cell culture supernatant by serial centrifugation and density-based separation. Characterization of EVs by electron microscopy and immunoblot analysis revealed vesicles 20 to 300 nm in size, which are positive for various EV marker proteins such as Rab5a and Hsp70. Proteome analysis via mass spectrometry indicated differences in the composition of plasma derived EVs and peripheral blood mononuclear cells (PBMCs) from the respective patient, as well as between plasma derived EVs from healthy donors compared to CLL patients. Regarding the later, CLL EVs were specifically enriched for proteins involved in antigen presentation, endocytosis signaling as well as integrin mediated signaling and leukocyte extravasation. RNA analysis by BioAnalyzer profiling indicated an enrichment of small RNAs in EVs compared to cells. Subsequent small RNA sequencing revealed a unique microRNA signature of MEC-1 EVs with the 5 most abundant miRNAs encompassing about 60% of all detected miRNAs. Among them, the CLL-relevant miR-21 and miR-155, as well as miR-146a were selectively enriched in EVs. Moreover, Y RNAs, another class of small non-coding, regulatory RNAs, were highly enriched in MEC-1 EVs and their presence was also observed in plasma EVs of CLL patients. We uncovered a rapid uptake of CLL cell-derived EVs by human monocytes and macrophages. Whether the identified proteins and RNA transcripts shown to be enriched in CLL EVs induce phenotypic changes in targeted cells is being investigated. Further, quantification of plasma EVs in a large cohort of CLL patients is currently conducted and differences in the amount of EVs in correlation to disease outcome are analyzed. Harboring a distinct RNA and protein profile, EVs are potent vehicles for shuttling RNA and proteins to recipient cells and might be involved in the establishment of a supportive microenvironment in CLL. Functional analyses regarding possible effects of CLL EVs on target cells will broaden the knowledge of CLL pathogenesis and might help to identify new therapeutic options for CLL. Disclosures No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V124.21.1968.1968
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2014
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  • 4
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    Exosomes released by chronic lymphocytic leukemia cells induce the transition of stromal cells into cancer-associated fibroblasts
    American Society of Hematology ; 2015
    In:  Blood Vol. 126, No. 9 ( 2015-08-27), p. 1106-1117
    Details
    In: Blood, American Society of Hematology, Vol. 126, No. 9 ( 2015-08-27), p. 1106-1117
    Abstract: CLL-derived exosomes are internalized by stromal cells, deliver functional microRNA and proteins, and activate key signaling pathways. Stromal cells exposed to CLL-derived exosomes demonstrate a CAF-like phenotype and secrete factors promoting CLL cell survival.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood-2014-12-618025
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2015
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  • 5
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    Abstract 5354: 3-phosphoinositide-dependent kinase-1 (PDK1, PDPK1) is a driver of osimertinib acquired resistance in EGFR mutant NSCLC
    American Association for Cancer Research (AACR) ; 2022
    In:  Cancer Research Vol. 82, No. 12_Supplement ( 2022-06-15), p. 5354-5354
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 82, No. 12_Supplement ( 2022-06-15), p. 5354-5354
    Abstract: Osimertinib, the only third-generation EGFR-TKI, showed incomplete responses to T790M-mutant NSCLC due to acquired resistance caused by activation of bypass pathways. We developed osimertinib-acquired resistant H1975-OSIR (T790M/L858R mutant) isogenic cells and TC386-OSIR isogenic PDXs. Neither H1975-OSIR nor TC386-OSIR PDXs developed additional mutations in EGFR. The H1975-OSIR clone showed 100 fold higher resistance to osimertinib compared with H1975 cells. TC386-OSIR PDX was developed through continuous in-vivo treatment for 8 months and the residual PDXs were passaged for several generations under continuous osimertinib treatment. TC386-OSIR fourth resistant generation (RG4) showed significantly higher resistance than initial generations (RG1). H1975-OSIR xenografts were developed in non-humanized and humanized NSG mice under osimertinib pressure. H1975-OsiR tumors were significantly less sensitive to osimertinib than their parental counterparts in both mouse models. Dose dependent antitumor activity of osimertinib (5mg/kg and 10mg/kg) was observed in H1975-parental tumors, whereas no treatment effect was observed for H1975-OsiR tumors with increasing doses. The tumor microenvironment was enriched with higher infiltration of tumor associated macrophages (TAM) and lower numbers of tumor infiltrating lymphocytes (TIL) in H1975-OSIR vs H1975 tumors. RPPA analysis of residual tumor tissues showed a distinct set of proteins upregulated in H1975-OsiR vs H1975-parental, among which PDK1 was the most upregulated. PDK1 was also significantly upregulated in H1975-OsiR tumors treated with osimertinib vs controls. PDK1 was not altered in any treatment groups in H1975-parental tumors. PDK1 and pPDK1 expression was many-fold higher in both H1975-OSIR cells and TC386-OSIR PDXs as compared to their parental counterparts by western blot and mass spec proteomics. Selective inhibition by the PDK inhibitor, BX 795, and CRISPR knock-out (KO) restored osimertinib sensitivity in resistant cells. Colony forming assays showed that the PDK1 KO clone was as sensitive as H1975-parental cells whereas a PDK overexpressing clone (OE) restored resistance. In-vivo inhibition of PDK1 by treating mice with BX-795 in both H1975-OSIR xenografts and TC386-OSIR PDXs significantly enhanced the antitumor activity of osimertinib. PDK1 KO dysregulated PI3K/Akt/mTOR signaling by downregulating Akt and mTOR phosphorylation and promoted cell cycle arrest at the G1 phase. NCI-H1975-OSIR and PDK1 OE cells showed a high level of nuclear localization of the activated Yes-associated protein pYAP(Y357). PDK1 KO cells significantly reduced nuclear localization of pYAP(Y357). The level of YAP and pYAP was upregulated in osimertinib resistant xenograft tumors and residual tumor biopsies. Taken together, we identified PDK1 as a drug able target to treat osimertinib acquired resistance. Citation Format: Ismail M. Meraz, Mourad Majidi, Bingliang Fang, Feng Meng, Lihui Gao, RuPing Shao, Renduo Song, Feng Li, Min Jin Ha, Qi Wang, Jing Wang, Elizabeth Shpall, Sung Yun Jung, Franziska Haderk, Philippe Gui, Jonathan W. Riess, Victor Olivas, Trever G. Bivona, Jack A. Roth. 3-phosphoinositide-dependent kinase-1 (PDK1, PDPK1) is a driver of osimertinib acquired resistance in EGFR mutant NSCLC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5354.
    Type of Medium: Online Resource
    ISSN: 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2022-5354
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2022
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  • 6
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    Abstract 3993: Efficacy of SHP2 phosphatase inhibition in cancers with nucleotide-cycling oncogenic RAS, NF1 loss and RAS-GTP-dependent oncogenic BRAF
    American Association for Cancer Research (AACR) ; 2018
    In:  Cancer Research Vol. 78, No. 13_Supplement ( 2018-07-01), p. 3993-3993
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 78, No. 13_Supplement ( 2018-07-01), p. 3993-3993
    Abstract: Oncogenic alterations in the RAS-RAF-MEK-ERK pathway, including mutant forms of KRAS, BRAF, and loss of the tumor suppressor and RAS GTPase-activating protein (GAP) NF1, drive the growth of a wide spectrum of cancers. While BRAF and MEK inhibitors are efficacious against BRAFV600E-driven cancers, effective targeted therapies are lacking for most cancers driven by other pathway alterations, including oncogenic KRAS, NF1 loss, and non-V600E oncogenic BRAF. Here, we show that targeting the PTPN11/SHP2 phosphatase with a novel small molecule allosteric inhibitor is effective in human cancer models bearing nucleotide-cycling oncogenic RAS (e.g. KRASG12C), NF1 loss, or RAS-GTP dependent oncogenic BRAF (e.g. class 3 BRAF mutants). SHP2 inhibitor treatment decreases oncogenic RAS-RAF-MEK-ERK signaling and cancer growth by disrupting SOS1-mediated RAS-GTP loading. Our findings illuminate a critical function for SHP2 in promoting oncogenic RAS activation and downstream signaling in cancers with nucleotide-cycling oncogenic RAS, RAS-GTP dependent oncogenic BRAF, and NF1 loss. SHP2 inhibition is a promising molecular therapeutic strategy for patients with cancers bearing these oncogenic drivers. Citation Format: Trever G. Bivona, Robert Nichols, Franziska Haderk, Carlos Stahlhut,Christopher Schulze, Golzar Hemmati, David Wildes. Efficacy of SHP2 phosphatase inhibition in cancers with nucleotide-cycling oncogenic RAS, NF1 loss and RAS-GTP-dependent oncogenic BRAF [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3993.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2018-3993
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2018
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  • 7
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    CLL Exosome-Derived Y RNA hY4 Induces TLR7/8-Mediated Inflammation and PD-L1 Expression in Monocytes
    American Society of Hematology ; 2016
    In:  Blood Vol. 128, No. 22 ( 2016-12-02), p. 3217-3217
    Details
    In: Blood, American Society of Hematology, Vol. 128, No. 22 ( 2016-12-02), p. 3217-3217
    Abstract: Chronic lymphocytic leukemia (CLL) is a B-cell malignancy associated with an inflammatory milieu and impaired anti-tumor immunity. Both in human CLL samples and the Eµ-TCL1 mouse model of CLL, monocytes and macrophages were identified as key players in the involved processes, as they secrete immune regulatory cytokines and show enhanced expression of the immune checkpoint protein PD-L1 which is known to be involved in T-cell suppression. We recently showed that reactivation of T-cell activity using anti-PD-L1 antibodies controls leukemia development in mice and is associated with a normalization of CLL-associated immune defects. The current study aimed at unraveling the molecular mechanisms of CLL-induced changes in monocytes and macrophages and focused on CLL-derived exosomes and their role in the tumor microenvironment. Exosomes were isolated from blood plasma of CLL patients as well as culture supernatant of the CLL cell line MEC-1 by a serial centrifugation protocol. Characterization of isolated exosomes by electron microscopy, Nanoparticle Tracking Analysis (NTA), and Western blot analysis revealed vesicles, 30 to 350 nm in size, which were positive for various exosome marker proteins. Quantification of exosomes by NTA and ELISA indicated an enrichment of B-cell derived exosomes in plasma of CLL patients compared to healthy controls, although absolute exosome counts were not different. RNA sequencing and proteome analysis of CLL exosomes revealed a disease-specific composition and identified non-coding Y RNA hY4 as the most abundant exosomal RNA species. Transfer of CLL exosomes or hY4 RNA alone to monocytes triggered release of cytokines like CCL2, CCL3, CCL4, and IL-6, and increased expression of PD-L1. As these are key features associated with CLL, a novel role for exosomal Y RNAs in the tumor microenvironment of CLL is suggested. Of interest, exosome or hY4-induced responses in monocytes were significantly reduced by chloroquine treatment and completely abolished in TLR7-deficient monocytes. Therefore, exosomal hY4 was identified as novel ligand that activates Toll-like receptor 7/8 signaling pathway in monocytes. Tumor-derived exosomes as well as exosomal Y RNAs were detected in a number of malignancies, suggesting their more general contribution to cancer-related sterile inflammation and the formation of a tumor-supportive myeloid microenvironment. Ongoing studies will show whether these novel findings can be exploited in treatment approaches for CLL and other malignancies. Disclosures Stilgenbauer: Hoffmann-La Roche: Consultancy, Honoraria, Other: Travel grants , Research Funding; Sanofi: Consultancy, Honoraria, Other: Travel grants , Research Funding; Pharmacyclics: Consultancy, Honoraria, Other: Travel grants , Research Funding; Boehringer Ingelheim: Consultancy, Honoraria, Other: Travel grants , Research Funding; AbbVie: Consultancy, Honoraria, Other: Travel grants, Research Funding; Novartis: Consultancy, Honoraria, Other: Travel grants , Research Funding; Janssen: Consultancy, Honoraria, Other: Travel grants , Research Funding; Genentech: Consultancy, Honoraria, Other: Travel grants , Research Funding; Amgen: Consultancy, Honoraria, Other: Travel grants, Research Funding; GSK: Consultancy, Honoraria, Other: Travel grants , Research Funding; Mundipharma: Consultancy, Honoraria, Other: Travel grants , Research Funding; Genzyme: Consultancy, Honoraria, Other: Travel grants , Research Funding; Gilead: Consultancy, Honoraria, Other: Travel grants , Research Funding; Celgene: Consultancy, Honoraria, Other: Travel grants , Research Funding.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V128.22.3217.3217
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2016
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  • 8
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    Understanding Drug Sensitivity and Tackling Resistance in Cancer
    American Association for Cancer Research (AACR) ; 2022
    In:  Cancer Research Vol. 82, No. 8 ( 2022-04-15), p. 1448-1460
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 82, No. 8 ( 2022-04-15), p. 1448-1460
    Abstract: Decades of research into the molecular mechanisms of cancer and the development of novel therapeutics have yielded a number of remarkable successes. However, our ability to broadly assign effective, rationally targeted therapies in a personalized manner remains elusive for many patients, and drug resistance persists as a major problem. This is in part due to the well-documented heterogeneity of cancer, including the diversity of tumor cell lineages and cell states, the spectrum of somatic mutations, the complexity of microenvironments, and immune-suppressive features and immune repertoires, which collectively require numerous different therapeutic approaches. Here, we describe a framework to understand the types and biological causes of resistance, providing translational opportunities to tackle drug resistance by rational therapeutic strategies.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/0008-5472.CAN-21-3695
    RVK:
    XA 36000
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    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2022
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  • 9
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    Abstract 2197: Targeted cancer therapy induces APOBEC fueling the evolution of drug resistance
    American Association for Cancer Research (AACR) ; 2022
    In:  Cancer Research Vol. 82, No. 12_Supplement ( 2022-06-15), p. 2197-2197
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 82, No. 12_Supplement ( 2022-06-15), p. 2197-2197
    Abstract: Introduction: Increasing our understanding of drivers of mutagenesis in lung cancer is critical in our efforts to prevent tumor reoccurrence and resistance. Results: Using the multi-region TRACERx lung cancer study, we uncovered that APOBEC3B is significantly upregulated when compared with other APOBEC family members in EGFR driven lung cancer and identified subclonal enrichment of APOBEC mutational signatures. To model APOBEC mutagenesis in lung cancer, several novel EGFR mutant mouse models containing a human APOBEC3B transgene were generated. Using these models, it was uncovered that APOBEC3B expression is detrimental at tumor initiation when expressed continuously in a p53 wildtype background. This detrimental effect is likely due to elevated chromosomal instability, which was observed to increase significantly with APOBEC3B expression in an EGFR mutant TP53 deficient mouse model. Induction of subclonal expression of APOBEC3B in an EGFR mutant mouse model with tyrosine kinase inhibitor (TKI) therapy resulted in a significant increase in resistant tumor development. Significant downregulation of the base excision repair gene uracil-DNA glycosylase (UNG) was also observed in APOBEC3B expressing mice, which paralleled findings in patient tumors and cell lines treated with TKI therapy. Finally, a mouse mutational signature was identified in APOBEC3B expressing cell lines, reinforcing the idea that APOBEC driven mutagenesis contributes to TKI resistance. Conclusion: This study demonstrates a unique principle by which targeted therapy induces changes within tumors ideal for APOBEC driven tumor evolution, fueling therapy resistance. Citation Format: Manasi Mayekar, Deborah Caswell, Natalie Vokes, Emily K. Law, Wei Wu, William Hill, Eva Gronroos, Andrew Rowan, Maise Al Bakir, Clare Weeden, Caroline E. McCoach, Collin M. Blakely, Nuri Alpay Temiz, Ai Nagano, Daniel L. Kerr, Julia K. Rotow, Oriol Pich, Franziska Haderk, Michelle Dietzen, Carlos Martinez Ruiz, Bruna Almeida, Lauren Cech, Beatrice Gini, Joanna Przewrocka, Chris Moore, Miguel Murillo, Bjorn Bakker, Brandon Rule, Cameron Durfee, Shigeki Nanj, Lisa Tan, Lindsay K. Larson, Prokopios P. Argyris, William L. Brown, Johnny Yu, Carlos Gomez, Philippe Gui, Rachel I. Vogel, Elizabeth A. Yu, Nicholas J. Thomas, Subramanian Venkatesan, Sebastijan Hobor, Su Kit Chew, Nicholas McGranahan, Nnennaya Kanu, Eliezer M. Van Allen, Julian Downward, Reuben S. Harris, Trever Bivona, Charles Swanton. Targeted cancer therapy induces APOBEC fueling the evolution of drug resistance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2197.
    Type of Medium: Online Resource
    ISSN: 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2022-2197
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2022
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  • 10
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    Abstract A30: Chronic lymphocytic leukemia-derived extracellular vesicles mediate NFkB signaling and pro-inflammatory cytokine release in monocytes
    American Association for Cancer Research (AACR) ; 2016
    In:  Cancer Research Vol. 76, No. 15_Supplement ( 2016-08-01), p. A30-A30
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 76, No. 15_Supplement ( 2016-08-01), p. A30-A30
    Abstract: The pathogenesis of chronic lymphocytic leukemia (CLL) is stringently associated with a tumor-supportive microenvironment and a dysfunctional immune system. Extracellular vesicles (EV) released by CLL cells are taken up by non-malignant cells in the microenvironment and mediate major disease-related changes in recipient cells. In the current study, we characterized CLL EVs, especially focusing on vesicle-incorporated RNA transcripts, and defined the role of CLL EVs in changing the myeloid tumor microenvironment. EVs were isolated from blood plasma of CLL patients and healthy donors as well as from supernatant of the CLL cell line MEC-1 by a serial centrifugation protocol. Characterization of EVs by electron microscopy, Nanoparticle Tracking Analysis (NTA) and Western blotting revealed vesicles 30 to 350 nm in size, which are positive for various EV marker proteins such as Rab5a and Hsp70. Quantification of blood plasma-derived EVs indicated an enrichment of B-cell derived EVs in plasma of CLL patients compared to healthy donors, although absolute EV counts were not altered in CLL. Focusing on RNA analysis, an enrichment of small RNAs in EVs was observed. Subsequent small RNA sequencing revealed a unique microRNA signature of MEC-1 EVs, with CLL-relevant miRNAs such as miR-21, miR-155 and miR-146a being the most abundant miRNAs. Moreover, full length and 5'end fragment forms of Y RNAs, another class of small non-coding RNAs, were enriched in MEC-1 EVs and CLL plasma EVs. Further evaluating the functional relevance of CLL EVs within the tumor microenvironment, a rapid uptake of CLL cell-derived EVs by human monocytes and macrophages was observed. Uptake of CLL EVs in monocytes induced NFkB signaling and the release of multiple pro-inflammatory cytokines such as CCL2, CCL3, IL-6 and IL-8, which are also upregulated in plasma of CLL patients. In conclusion, tumor-derived EVs harbor a distinct set of non-coding RNAs. The uptake of EVs in recipient cells and the concomitant transfer of incorporated RNAs mediate substantial phenotypic changes in target cells. In the current study, this is exemplified for monocytes, which present several disease-relevant alterations upon EV uptake, including cellular activation and secretion of pro-inflammatory cytokines. Citation Format: Franziska Haderk, Laura Llao Cid, Etienne Moussay, Jerome Paggetti, Karolin Willmund, Jana Seiler, Sven Diederichs, Maria Goebel, Jan Duerig, Thorsten Zenz, Stephan Stilgenbauer, Marc Zapatka, Peter Lichter, Martina Seiffert. Chronic lymphocytic leukemia-derived extracellular vesicles mediate NFkB signaling and pro-inflammatory cytokine release in monocytes. [abstract] . In: Proceedings of the AACR Special Conference: Function of Tumor Microenvironment in Cancer Progression; 2016 Jan 7–10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2016;76(15 Suppl):Abstract nr A30.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.TME16-A30
    RVK:
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    RVK:
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    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2016
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