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      Mitochondrial permeabilisation engages NF-κB dependent anti-tumour activity under caspase deficiency

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          Abstract

          Apoptosis represents a key anti-cancer therapeutic effector mechanism. During apoptosis, mitochondrial outer membrane permeabilisation (MOMP) typically kills cells even in the absence of caspase activity. Caspase activity can also have a variety of unwanted consequences that include DNA-damage. We therefore investigated whether MOMP-induced caspase-independent cell death (CICD) might be a better way to kill cancer cells. We find that cells undergoing CICD display potent pro-inflammatory effects relative to apoptosis. Underlying this, MOMP was found to stimulate NF-κB activity through the down-regulation of inhibitor of apoptosis (IAP) proteins. Strikingly, engagement of CICD displays potent anti-tumorigenic effects, often promoting complete tumour regression in a manner dependent on intact immunity. Our data demonstrate that by activating NF-κB, MOMP can exert additional signalling functions besides triggering cell death. Moreover, they support a rationale for engaging caspase-independent cell death in cell-killing anti-cancer therapies.

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          Most cited references45

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          Improved vectors and genome-wide libraries for CRISPR screening.

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            Genome-scale CRISPR-Cas9 knockout screening in human cells.

            The simplicity of programming the CRISPR (clustered regularly interspaced short palindromic repeats)-associated nuclease Cas9 to modify specific genomic loci suggests a new way to interrogate gene function on a genome-wide scale. We show that lentiviral delivery of a genome-scale CRISPR-Cas9 knockout (GeCKO) library targeting 18,080 genes with 64,751 unique guide sequences enables both negative and positive selection screening in human cells. First, we used the GeCKO library to identify genes essential for cell viability in cancer and pluripotent stem cells. Next, in a melanoma model, we screened for genes whose loss is involved in resistance to vemurafenib, a therapeutic RAF inhibitor. Our highest-ranking candidates include previously validated genes NF1 and MED12, as well as novel hits NF2, CUL3, TADA2B, and TADA1. We observe a high level of consistency between independent guide RNAs targeting the same gene and a high rate of hit confirmation, demonstrating the promise of genome-scale screening with Cas9.
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              Macrophage plasticity and interaction with lymphocyte subsets: cancer as a paradigm.

              Plasticity is a hallmark of cells of the myelomonocytic lineage. In response to innate recognition or signals from lymphocyte subsets, mononuclear phagocytes undergo adaptive responses. Shaping of monocyte-macrophage function is an essential component of resistance to pathogens, tissue damage and repair. The orchestration of myelomonocytic cell function is a key element that links inflammation and cancer and provides a paradigm for macrophage plasticity and function. A better understanding of the molecular basis of myelomonocytic cell plasticity will open new vistas in immunopathology and therapeutic intervention.
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                Author and article information

                Journal
                100890575
                21417
                Nat Cell Biol
                Nat. Cell Biol.
                Nature cell biology
                1465-7392
                1476-4679
                18 September 2017
                28 August 2017
                September 2017
                28 February 2018
                : 19
                : 9
                : 1116-1129
                Affiliations
                [1 ]Cancer Research UK Beatson Institute
                [2 ]Institute of Cancer Sciences, University of Glasgow, Garscube Estate, Switchback Road, Glasgow, G61 1BD, U.K.
                [3 ]Université Côte d’Azur, Inserm, C3M, France
                [4 ]Laboratory of Dendritic Cell Biology, Department of Immunology, Institut Pasteur, 25 Rue du Docteur Roux, 75015 Paris, France
                [5 ]Molecular & Cellular Biology Program and Dept. of Immunology, University of Washington, 750 Republican St., Seattle, WA 981, U.S.A.
                [6 ]Centre for Cell Death, Cancer and Inflammation, UCL Cancer Institute, UCL, London WC1E 6BT, UK
                [7 ]Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan 20133, Italy
                [8 ]Department of Cancer Immunology, Genentech Inc., 1 DNA way, South San Francisco, California 94080, USA
                [9 ]Centre for Immunobiology, Institute for Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, U.K.
                Author notes
                [* ]Correspondence should be addressed to (S.W.G.T): stephen.tait@ 123456glasgow.ac.uk
                [^]

                Present address: University of Lyon, Cancer Research Centre of Lyon (CRCL), UMR INSERM 1052 CNRS 5286, Léon Bérard Centre, 28, Rue Laennec, 69008, Lyon, France.

                Article
                EMS73487
                10.1038/ncb3596
                5624512
                28846096
                7fe7e50e-8f6f-488b-9826-46e669a36acf

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                Cell biology
                Cell biology

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