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  • 1
    Publication Date: 2014-04-18
    Description: Centrosome amplification has long been recognized as a feature of human tumours; however, its role in tumorigenesis remains unclear. Centrosome amplification is poorly tolerated by non-transformed cells and, in the absence of selection, extra centrosomes are spontaneously lost. Thus, the high frequency of centrosome amplification, particularly in more aggressive tumours, raises the possibility that extra centrosomes could, in some contexts, confer advantageous characteristics that promote tumour progression. Using a three-dimensional model system and other approaches to culture human mammary epithelial cells, we find that centrosome amplification triggers cell invasion. This invasive behaviour is similar to that induced by overexpression of the breast cancer oncogene ERBB2 (ref. 4) and indeed enhances invasiveness triggered by ERBB2. Our data indicate that, through increased centrosomal microtubule nucleation, centrosome amplification increases Rac1 activity, which disrupts normal cell-cell adhesion and promotes invasion. These findings demonstrate that centrosome amplification, a structural alteration of the cytoskeleton, can promote features of malignant transformation.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4061398/" 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/PMC4061398/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Godinho, Susana A -- Picone, Remigio -- Burute, Mithila -- Dagher, Regina -- Su, Ying -- Leung, Cheuk T -- Polyak, Kornelia -- Brugge, Joan S -- Thery, Manuel -- Pellman, David -- 310472/European Research Council/International -- GM083299-1/GM/NIGMS NIH HHS/ -- R01 GM083299/GM/NIGMS NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2014 Jun 5;510(7503):167-71. doi: 10.1038/nature13277. Epub 2014 Apr 13.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Howard Hughes Medical Institute, Department of Pediatric Oncology, Dana-Farber Cancer Institute and Pediatric Hematology/Oncology, Children's Hospital, Boston, Massachusetts 02115, USA [2] Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, USA [3] Barts Cancer Institute, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, UK (S.A.G.); Department of Pharmacology, University of Minnesota, Minneapolis, Minnesota 55455, USA (C.T.L.). ; 1] Howard Hughes Medical Institute, Department of Pediatric Oncology, Dana-Farber Cancer Institute and Pediatric Hematology/Oncology, Children's Hospital, Boston, Massachusetts 02115, USA [2] Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, USA. ; 1] Institut de Recherche en Technologie et Science pour le Vivant, UMR5168 CEA/UJF/INRA/CNRS, Grenoble, France [2] Hopital Saint Louis, Institut Universitaire d'Hematologie, U1160 INSERM/AP-HP/Universite Paris Diderot, Paris 75010, France [3] CYTOO SA, Grenoble 38054, France. ; Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115, USA. ; 1] Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, USA [2] Barts Cancer Institute, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, UK (S.A.G.); Department of Pharmacology, University of Minnesota, Minneapolis, Minnesota 55455, USA (C.T.L.). ; Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, USA. ; 1] Institut de Recherche en Technologie et Science pour le Vivant, UMR5168 CEA/UJF/INRA/CNRS, Grenoble, France [2] Hopital Saint Louis, Institut Universitaire d'Hematologie, U1160 INSERM/AP-HP/Universite Paris Diderot, Paris 75010, France.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24739973" target="_blank"〉PubMed〈/a〉
    Keywords: Aneuploidy ; Breast/cytology/pathology ; Breast Neoplasms/genetics/*pathology ; Cell Adhesion ; Cell Line ; Cell Transformation, Neoplastic/genetics/*pathology ; Centrosome/*pathology ; Disease Progression ; Enzyme Activation ; Epithelial Cells/cytology/pathology ; *Genes, erbB-2 ; Humans ; Microtubules/chemistry/metabolism/pathology ; Neoplasm Invasiveness/pathology ; Receptor, ErbB-2/genetics/metabolism ; rac1 GTP-Binding Protein/metabolism
    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: 2015-05-29
    Description: Genome sequencing has uncovered a new mutational phenomenon in cancer and congenital disorders called chromothripsis. Chromothripsis is characterized by extensive genomic rearrangements and an oscillating pattern of DNA copy number levels, all curiously restricted to one or a few chromosomes. The mechanism for chromothripsis is unknown, but we previously proposed that it could occur through the physical isolation of chromosomes in aberrant nuclear structures called micronuclei. Here, using a combination of live cell imaging and single-cell genome sequencing, we demonstrate that micronucleus formation can indeed generate a spectrum of genomic rearrangements, some of which recapitulate all known features of chromothripsis. These events are restricted to the mis-segregated chromosome and occur within one cell division. We demonstrate that the mechanism for chromothripsis can involve the fragmentation and subsequent reassembly of a single chromatid from a micronucleus. Collectively, these experiments establish a new mutational process of which chromothripsis is one extreme outcome.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4742237/" 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/PMC4742237/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Zhang, Cheng-Zhong -- Spektor, Alexander -- Cornils, Hauke -- Francis, Joshua M -- Jackson, Emily K -- Liu, Shiwei -- Meyerson, Matthew -- Pellman, David -- GM083299-18/GM/NIGMS NIH HHS/ -- R01 GM061345/GM/NIGMS NIH HHS/ -- R01 GM083299/GM/NIGMS NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2015 Jun 11;522(7555):179-84. doi: 10.1038/nature14493. Epub 2015 May 27.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA [2] Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA [3] Broad Institute of Harvard and MIT, Cambridge, Massachusetts 02142, USA [4] Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, USA. ; 1] Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA [2] Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, USA [3] Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA. ; 1] Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA [2] Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, USA. ; 1] Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA [2] Broad Institute of Harvard and MIT, Cambridge, Massachusetts 02142, USA. ; 1] Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA [2] Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, USA [3] Howard Hughes Medical Institute, Chevy Chase, Maryland 20815, USA. ; 1] Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA [2] Broad Institute of Harvard and MIT, Cambridge, Massachusetts 02142, USA [3] Department of Pathology, Harvard Medical School, Boston, Massachusetts 02115, USA [4] Center for Cancer Genome Discovery, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA. ; 1] Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA [2] Broad Institute of Harvard and MIT, Cambridge, Massachusetts 02142, USA [3] Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, USA [4] Howard Hughes Medical Institute, Chevy Chase, Maryland 20815, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26017310" target="_blank"〉PubMed〈/a〉
    Keywords: Cell Line ; Cell Survival ; *Chromosome Breakage ; Chromosome Segregation/genetics ; DNA Copy Number Variations/genetics ; *DNA Damage ; Gene Rearrangement/genetics ; Genomic Instability/genetics ; Humans ; *Micronuclei, Chromosome-Defective ; Mutation/genetics ; Neoplasms/genetics ; S Phase/genetics ; Single-Cell Analysis
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 3
    Publication Date: 2012-01-20
    Description: The involvement of whole-chromosome aneuploidy in tumorigenesis is the subject of debate, in large part because of the lack of insight into underlying mechanisms. Here we identify a mechanism by which errors in mitotic chromosome segregation generate DNA breaks via the formation of structures called micronuclei. Whole-chromosome-containing micronuclei form when mitotic errors produce lagging chromosomes. We tracked the fate of newly generated micronuclei and found that they undergo defective and asynchronous DNA replication, resulting in DNA damage and often extensive fragmentation of the chromosome in the micronucleus. Micronuclei can persist in cells over several generations but the chromosome in the micronucleus can also be distributed to daughter nuclei. Thus, chromosome segregation errors potentially lead to mutations and chromosome rearrangements that can integrate into the genome. Pulverization of chromosomes in micronuclei may also be one explanation for 'chromothripsis' in cancer and developmental disorders, where isolated chromosomes or chromosome arms undergo massive local DNA breakage and rearrangement.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3271137/" 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/PMC3271137/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Crasta, Karen -- Ganem, Neil J -- Dagher, Regina -- Lantermann, Alexandra B -- Ivanova, Elena V -- Pan, Yunfeng -- Nezi, Luigi -- Protopopov, Alexei -- Chowdhury, Dipanjan -- Pellman, David -- 1R01CA142698-01/CA/NCI NIH HHS/ -- GM083299/GM/NIGMS NIH HHS/ -- R00 CA154531/CA/NCI NIH HHS/ -- R01 CA142698/CA/NCI NIH HHS/ -- R01 GM083299/GM/NIGMS NIH HHS/ -- R01 GM083299-14/GM/NIGMS NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2012 Jan 18;482(7383):53-8. doi: 10.1038/nature10802.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Pediatric Oncology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, Massachusetts 02115, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22258507" target="_blank"〉PubMed〈/a〉
    Keywords: *Aneuploidy ; Cell Line, Tumor ; Cell Transformation, Neoplastic/genetics/pathology ; *Chromosome Breakage ; Chromosome Segregation ; Comet Assay ; DNA Fragmentation ; DNA Replication ; Humans ; *Micronuclei, Chromosome-Defective ; *Mitosis/genetics ; Neoplasms/etiology/genetics/pathology
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 4
    Publication Date: 2015-03-04
    Description: Polyploidy is observed across the tree of life, yet its influence on evolution remains incompletely understood. Polyploidy, usually whole-genome duplication, is proposed to alter the rate of evolutionary adaptation. This could occur through complex effects on the frequency or fitness of beneficial mutations. For example, in diverse cell types and organisms, immediately after a whole-genome duplication, newly formed polyploids missegregate chromosomes and undergo genetic instability. The instability following whole-genome duplications is thought to provide adaptive mutations in microorganisms and can promote tumorigenesis in mammalian cells. Polyploidy may also affect adaptation independently of beneficial mutations through ploidy-specific changes in cell physiology. Here we perform in vitro evolution experiments to test directly whether polyploidy can accelerate evolutionary adaptation. Compared with haploids and diploids, tetraploids undergo significantly faster adaptation. Mathematical modelling suggests that rapid adaptation of tetraploids is driven by higher rates of beneficial mutations with stronger fitness effects, which is supported by whole-genome sequencing and phenotypic analyses of evolved clones. Chromosome aneuploidy, concerted chromosome loss, and point mutations all provide large fitness gains. We identify several mutations whose beneficial effects are manifest specifically in the tetraploid strains. Together, these results provide direct quantitative evidence that in some environments polyploidy can accelerate evolutionary adaptation.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4497379/" 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/PMC4497379/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Selmecki, Anna M -- Maruvka, Yosef E -- Richmond, Phillip A -- Guillet, Marie -- Shoresh, Noam -- Sorenson, Amber L -- De, Subhajyoti -- Kishony, Roy -- Michor, Franziska -- Dowell, Robin -- Pellman, David -- R01 GM081617/GM/NIGMS NIH HHS/ -- R37 GM061345/GM/NIGMS NIH HHS/ -- R37 GM61345/GM/NIGMS NIH HHS/ -- U54CA143798/CA/NCI NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2015 Mar 19;519(7543):349-52. doi: 10.1038/nature14187. Epub 2015 Mar 2.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Department of Pediatric Oncology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, Massachusetts 02215, USA [2] Department of Cell Biology, Harvard Medical School, 25 Shattuck Street, Boston, Massachusetts 02215, USA [3] Howard Hughes Medical Institute, 4000 Jones Bridge Road, Chevy Chase, Maryland 20815, USA. ; 1] Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, 450 Brookline Avenue Boston, Massachusetts 02215, USA [2] Department of Biostatistics, Harvard School of Public Health, 158 Longwood Avenue, Boston, Massachusetts 02215, USA. ; 1] BioFrontiers Institute, University of Colorado at Boulder, 3415 Colorado Avenue, Boulder, Colorado 80303, USA [2] Department of Molecular, Cellular and Developmental Biology, University of Colorado at Boulder, 347 UCB, Boulder, Colorado 80309, USA. ; Broad Institute, 415 Main Street, Cambridge, Massachusetts 02142, USA. ; 1] Department of Medicine, University of Colorado School of Medicine, 13001 East 17th Place, Aurora, Colorado 80045, USA [2] Department of Biostatistics and Informatics, Colorado School of Public Health, 13001 East 17th Place, Aurora, Colorado 80045, USA [3] Molecular Oncology Program, University of Colorado Cancer Center, 13001 East 17th Place, Aurora, Colorado 80045, USA. ; 1] Department of Systems Biology, Harvard Medical School, 200 Longwood Ave, Boston, Massachusetts 02115, USA [2] Department of Biology, Technion - Israel Institute of Technology, Haifa, 32000, Israel. ; 1] Department of Pediatric Oncology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, Massachusetts 02215, USA [2] Department of Cell Biology, Harvard Medical School, 25 Shattuck Street, Boston, Massachusetts 02215, USA [3] Howard Hughes Medical Institute, 4000 Jones Bridge Road, Chevy Chase, Maryland 20815, USA [4] Department of Pediatric Hematology/Oncology, Children's Hospital, 300 Longwood Avenue, Boston, Massachusetts 02115, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25731168" target="_blank"〉PubMed〈/a〉
    Keywords: Adaptation, Physiological/*genetics ; Aneuploidy ; *Biological Evolution ; Chromosomes, Fungal/genetics ; Clone Cells/cytology/metabolism ; Diploidy ; Genetic Fitness/genetics ; Haploidy ; Mutation Rate ; Point Mutation/genetics ; *Polyploidy ; Saccharomyces cerevisiae/cytology/*genetics/metabolism/*physiology ; Time Factors
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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