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  • 1
    Publication Date: 2014-08-15
    Description: Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest cancers in western countries, with a median survival of 6 months and an extremely low percentage of long-term surviving patients. KRAS mutations are known to be a driver event of PDAC, but targeting mutant KRAS has proved challenging. Targeting oncogene-driven signalling pathways is a clinically validated approach for several devastating diseases. Still, despite marked tumour shrinkage, the frequency of relapse indicates that a fraction of tumour cells survives shut down of oncogenic signalling. Here we explore the role of mutant KRAS in PDAC maintenance using a recently developed inducible mouse model of mutated Kras (Kras(G12D), herein KRas) in a p53(LoxP/WT) background. We demonstrate that a subpopulation of dormant tumour cells surviving oncogene ablation (surviving cells) and responsible for tumour relapse has features of cancer stem cells and relies on oxidative phosphorylation for survival. Transcriptomic and metabolic analyses of surviving cells reveal prominent expression of genes governing mitochondrial function, autophagy and lysosome activity, as well as a strong reliance on mitochondrial respiration and a decreased dependence on glycolysis for cellular energetics. Accordingly, surviving cells show high sensitivity to oxidative phosphorylation inhibitors, which can inhibit tumour recurrence. Our integrated analyses illuminate a therapeutic strategy of combined targeting of the KRAS pathway and mitochondrial respiration to manage pancreatic cancer.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4376130/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4376130/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Viale, Andrea -- Pettazzoni, Piergiorgio -- Lyssiotis, Costas A -- Ying, Haoqiang -- Sanchez, Nora -- Marchesini, Matteo -- Carugo, Alessandro -- Green, Tessa -- Seth, Sahil -- Giuliani, Virginia -- Kost-Alimova, Maria -- Muller, Florian -- Colla, Simona -- Nezi, Luigi -- Genovese, Giannicola -- Deem, Angela K -- Kapoor, Avnish -- Yao, Wantong -- Brunetto, Emanuela -- Kang, Ya'an -- Yuan, Min -- Asara, John M -- Wang, Y Alan -- Heffernan, Timothy P -- Kimmelman, Alec C -- Wang, Huamin -- Fleming, Jason B -- Cantley, Lewis C -- DePinho, Ronald A -- Draetta, Giulio F -- CA016672/CA/NCI NIH HHS/ -- CA16672/CA/NCI NIH HHS/ -- P01 CA117969/CA/NCI NIH HHS/ -- P01 CA120964/CA/NCI NIH HHS/ -- P01CA117969/CA/NCI NIH HHS/ -- P01CA120964/CA/NCI NIH HHS/ -- P30 CA016672/CA/NCI NIH HHS/ -- P30CA16672/CA/NCI NIH HHS/ -- P50 CA127003/CA/NCI NIH HHS/ -- England -- Nature. 2014 Oct 30;514(7524):628-32. doi: 10.1038/nature13611. Epub 2014 Aug 10.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA [2] Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA [3]. ; Department of Medicine, Weill Cornell Medical College, New York, New York 10065, USA. ; Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA. ; 1] Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA [2] Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA. ; 1] Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA [2] Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA [3] Department of Experimental Oncology, European Institute of Oncology, Milan 20139, Italy. ; Institute for Applied Cancer Science, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA. ; Pathology Unit, San Raffaele Scientific Institute, Milan 20132, Italy. ; Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA. ; Department of Medicine, Division of Signal Transduction, Beth Israel Deaconess Medical Center, Boston, Massachusetts 02115, USA. ; Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA. ; Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA. ; Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25119024" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Autophagy ; Carcinoma, Pancreatic Ductal/drug therapy/genetics/*metabolism/*pathology ; Cell Respiration/drug effects ; Cell Survival/drug effects ; Disease Models, Animal ; Female ; Gene Expression Regulation, Neoplastic ; Genes, p53/genetics ; Glycolysis ; Lysosomes/metabolism ; Mice ; Mitochondria/drug effects/*metabolism ; Mutation/genetics ; Neoplasm Recurrence, Local/prevention & control ; Neoplastic Stem Cells/drug effects/metabolism/pathology ; Oxidative Phosphorylation/drug effects ; Pancreatic Neoplasms/drug therapy/genetics/*metabolism/*pathology ; Proto-Oncogene Proteins p21(ras)/*genetics/metabolism ; Recurrence ; Signal Transduction
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 2
    Publication Date: 2014-02-18
    Description: A core promoter is a stretch of DNA surrounding the transcription start site (TSS) that integrates regulatory inputs and recruits general transcription factors to initiate transcription. The nature and causative relationship of the DNA sequence and chromatin signals that govern the selection of most TSSs by RNA polymerase II remain unresolved. Maternal to zygotic transition represents the most marked change of the transcriptome repertoire in the vertebrate life cycle. Early embryonic development in zebrafish is characterized by a series of transcriptionally silent cell cycles regulated by inherited maternal gene products: zygotic genome activation commences at the tenth cell cycle, marking the mid-blastula transition. This transition provides a unique opportunity to study the rules of TSS selection and the hierarchy of events linking transcription initiation with key chromatin modifications. We analysed TSS usage during zebrafish early embryonic development at high resolution using cap analysis of gene expression, and determined the positions of H3K4me3-marked promoter-associated nucleosomes. Here we show that the transition from the maternal to zygotic transcriptome is characterized by a switch between two fundamentally different modes of defining transcription initiation, which drive the dynamic change of TSS usage and promoter shape. A maternal-specific TSS selection, which requires an A/T-rich (W-box) motif, is replaced with a zygotic TSS selection grammar characterized by broader patterns of dinucleotide enrichments, precisely aligned with the first downstream (+1) nucleosome. The developmental dynamics of the H3K4me3-marked nucleosomes reveal their DNA-sequence-associated positioning at promoters before zygotic transcription and subsequent transcription-independent adjustment to the final position downstream of the zygotic TSS. The two TSS-defining grammars coexist, often physically overlapping, in core promoters of constitutively expressed genes to enable their expression in the two regulatory environments. The dissection of overlapping core promoter determinants represents a framework for future studies of promoter structure and function across different regulatory contexts.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Haberle, Vanja -- Li, Nan -- Hadzhiev, Yavor -- Plessy, Charles -- Previti, Christopher -- Nepal, Chirag -- Gehrig, Jochen -- Dong, Xianjun -- Akalin, Altuna -- Suzuki, Ana Maria -- van IJcken, Wilfred F J -- Armant, Olivier -- Ferg, Marco -- Strahle, Uwe -- Carninci, Piero -- Muller, Ferenc -- Lenhard, Boris -- MC_UP_1102/1/Medical Research Council/United Kingdom -- Medical Research Council/United Kingdom -- England -- Nature. 2014 Mar 20;507(7492):381-5. doi: 10.1038/nature12974. Epub 2014 Feb 16.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Department of Biology, University of Bergen, Thormohlensgate 53A, N-5008 Bergen, Norway [2] Institute of Clinical Sciences and MRC Clinical Sciences Center, Faculty of Medicine, Imperial College London, Hammersmith Hospital, Du Cane Road, London W12 0NN, UK [3]. ; 1] School of Clinical and Experimental Medicine, College of Medical and Dental Sciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK [2]. ; School of Clinical and Experimental Medicine, College of Medical and Dental Sciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK. ; 1] RIKEN Omics Science Center, Yokohama, Kanagawa 230-0045, Japan [2] RIKEN Center for Life Science Technologies, Division of Genomic Technologies, RIKEN Yokohama Campus, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama, Kanagawa 230-0045, Japan. ; 1] Computational Biology Unit, Uni Computing, Uni Research AS, University of Bergen, Thormohlensgate 55, N-5008 Bergen, Norway [2] German Cancer Research Center (DKFZ), Genomics & Proteomics Core Facility (GPCF), Im Neuenheimer Feld 580/TP3, Heidelberg 69120, Germany (C.Pr.); Broegelmann Research Laboratory, The Gade Institute, University of Bergen, The Laboratory Building, Haukeland University Hospital, N-5021 Bergen, Norway (C.N.); Acquifer AG, Sophienstrasse 136, 76135 Karlsruhe, Germany (J.G.); Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA (X.D.); Friedrich Miescher Institute for Biomedical Research, Maulbeerstrasse 66, 4058 Basel, Switzerland (A.A.). ; 1] School of Clinical and Experimental Medicine, College of Medical and Dental Sciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK [2] German Cancer Research Center (DKFZ), Genomics & Proteomics Core Facility (GPCF), Im Neuenheimer Feld 580/TP3, Heidelberg 69120, Germany (C.Pr.); Broegelmann Research Laboratory, The Gade Institute, University of Bergen, The Laboratory Building, Haukeland University Hospital, N-5021 Bergen, Norway (C.N.); Acquifer AG, Sophienstrasse 136, 76135 Karlsruhe, Germany (J.G.); Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA (X.D.); Friedrich Miescher Institute for Biomedical Research, Maulbeerstrasse 66, 4058 Basel, Switzerland (A.A.). ; Erasmus Medical Center, Center for Biomics, Room Ee679b, Dr Molewaterplein 50, 3015 GE Rotterdam, The Netherlands. ; Institute of Toxicology and Genetics, Karlsruhe Institute of Technology, Postfach 3640, 76021 Karlsruhe, Germany. ; 1] Institute of Clinical Sciences and MRC Clinical Sciences Center, Faculty of Medicine, Imperial College London, Hammersmith Hospital, Du Cane Road, London W12 0NN, UK [2] Department of Informatics, University of Bergen, Thormohlensgate 55, N-5008 Bergen, Norway.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24531765" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Base Sequence ; Embryo, Nonmammalian/embryology/metabolism ; Female ; Gene Expression Regulation, Developmental/genetics ; Histones/metabolism ; Methylation ; Mothers ; Nucleosomes/genetics ; Promoter Regions, Genetic/*genetics ; *Transcription Initiation Site ; Transcription Initiation, Genetic ; Transcriptome/genetics ; Zebrafish/embryology/*genetics ; Zygote/metabolism
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 3
    Electronic Resource
    Electronic Resource
    Amsterdam : Elsevier
    Free Radical Biology and Medicine 13 (1992), S. 651-657 
    ISSN: 0891-5849
    Keywords: AIDS ; Free radical ; Glutathione ; HIV ; Macrophage ; Monocyte ; NF-κB ; Oxidative burst
    Source: Elsevier Journal Backfiles on ScienceDirect 1907 - 2002
    Topics: Biology , Chemistry and Pharmacology , Medicine
    Type of Medium: Electronic Resource
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