2015
DOI: 10.7554/elife.05068
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Abstract: Cancer cells display aneuploid karyotypes and typically mis-segregate chromosomes at high rates, a phenotype referred to as chromosomal instability (CIN). To test the effects of aneuploidy on chromosome segregation and other mitotic phenotypes we used the colorectal cancer cell line DLD1 (2n = 46) and two variants with trisomy 7 or 13 (DLD1+7 and DLD1+13), as well as euploid and trisomy 13 amniocytes (AF and AF+13). We found that trisomic cells displayed higher rates of chromosome mis-segregation compared to t… Show more

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Cited by 89 publications
(86 citation statements)
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References 74 publications
(125 reference statements)
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“…Compared to the diploid parental line, the frequencies of chromosome missegregation and micronuclei formation were significantly elevated in most PTA clones ( Figure 2A ) but not in the tetraploid line ( Figure 2A ). In agreement with previous work ( Nicholson et al , 2015 ), the trisomic clones showed similar aberrations, albeit to a lesser extent (Supplemental Figure S2B). Furthermore, we observed an increase of structural aberrations in PTA lines and, consistent with earlier work ( Kuznetsova et al , 2015 ; Passerini et al , 2016 ), also in trisomic clones ( Figure 2B ).…”
Section: Resultssupporting
confidence: 93%
“…To independently confirm the observed chromosome instability, RPE +18+18 aneuploid cells were treated with dihydrocytochalasin B (DCB) to disrupt cytokinesis followed by FISH labelling using specific probes to identify chromosomes 13, 18 and 21 in the binucleated cells (Fig 2E and F). This method reveals the reciprocal distribution of labeled chromosomes between daughter nuclei immediately after chromosome segregation and can be applied to the analysis of several hundred cells in tandem [10]. As shown in Fig 2E and F, RPE +18+18 cells displayed a significant increase in chromosome mis-segregation rates, consistent with the results of our live-cell imaging analysis.…”
Section: Aneuploid Cell Lines Display Stable Karyotypes Despite Chromsupporting
confidence: 82%
“…Aneuploid karyotypes display different degrees of genome instability between model systems [8][9][10][11]. We therefore proceeded to test whether karyotype stability of the aneuploid lines obtained here was due to a high overall level of chromosomal integrity or could be attributed to growth restriction of the aberrant daughter cells.…”
Section: Aneuploid Cell Lines Display Stable Karyotypes Despite Chrommentioning
confidence: 99%
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“…This observation might seem surprising at first as there are many studies that showed that aneuploidy leads to CIN. However, the specific effects of monosomies versus trisomies on CIN have not been extensively explored before as most model systems studying the effects of aneuploidy solely involve chromosome gains [24,25,28,30]. Also, in contrast to our findings, it was recently documented that certain monosomies can in fact trigger a CIN phenotype [60].…”
Section: Monosomies Are Chromosomally Stablesupporting
(Expert classified)
“…While aneuploidy is a consequence of CIN, it remains controversial if aneuploidy per se can be an underlying cause of CIN. Some studies have indeed suggested that deviating karyotypes can instigate instability [24][25][26][27][28][29]. For instance, CIN has been suggested to be the result of specific gains or losses of chromosomes that contain key regulators of proper segregation in mitosis [25,30].…”
Section: Introductionmentioning
confidence: 99%
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“…In line with the data obtained in yeast, work in Chinese hamster embryo and human cells indicates that aneuploidy is associated with genome instability also in higher eukaryotes ( Li et al, 1997 ; Nawata et al, 2011 ; Nicholson et al, 2015 ). Indeed, HE35 cells with an extra copy of chromosome 8 display an increase in structural chromosomal aberrations ( Nawata et al, 2011 ).…”
Section: Aneuploidy Is Associated With Increasing Genome Instabilitysupporting
confidence: 76%
“…Indeed, HE35 cells with an extra copy of chromosome 8 display an increase in structural chromosomal aberrations ( Nawata et al, 2011 ). Also, a systematic comparison between trisomic and diploid human cells (both untransformed amniotic fibroblasts and colorectal cancer cells DLD1) has uncovered that aneuploidy is associated with increased frequency of anaphase lagging chromosomes and cytokinesis failure ( Nicholson et al, 2015 ).…”
Section: Aneuploidy Is Associated With Increasing Genome Instabilitymentioning
confidence: 99%
“…Importantly, these putative rates of chromosome mis-segregation fall within the range of approximated per chromosome rates experimentally observed in cancer cell lines and human tumors (Bakhoum et al, 2014(Bakhoum et al, , 2011(Bakhoum et al, , 2009Dewhurst et al, 2014;Nicholson et al, 2015;Orr et al, 2016;Thompson and Compton, 2008;Worrall et al, 2018;Zasadil et al, 2014). Higher inferred mis-segregation rates significantly correlated with lower inferred selection experienced in these samples (Figure 6F).…”
Section: Inferring Chromosome Mis-segregation Rates In Tumors and Organoidssupporting
confidence: 69%
“…Molecularly, cytokinesis failure in DLD1 cells containing an extra copy of chromosome 13 was attributed to overexpression of the gene encoding Spartin, a gene previously implicated in cytokinesis, which is located on chromosome 13. Consistent with this, overexpression of Spartin caused cytokinesis failure in control DLD1 cells while partial depletion of Spartin rescued cytokinesis failure in DLD1 cells and amniotic fibroblasts containing an extra copy of chromosome 13 (Nicholson et al, 2015). Thus, though there are common effects of aneuploidy, individual aneuploid karyotypes also have specific defects depending on the genes on the imbalanced chromosome(s).…”
Section: The Complex Relationship Between Aneuploidy and Chromosomal mentioning
(Expert classified)
“…Meiosis in yeast strains with an uneven ploidy (3n or 5n) results in the production of both stably aneuploid and CIN yeast strains, with CIN yeast strains predominating (Pavelka et al, 2010; Sheltzer et al, 2011; Zhu et al, 2012). Similarly, in human cells the addition of one copy of chromosome 7 (in the chromosomally stable colorectal cancer cell line DLD1) or one copy of chromosome 13 (in DLD1 cells or in amniotic fibroblasts) leads to increased rates of chromosome missegregation, predominantly of the triploid chromosome (Nicholson et al, 2015). Gain of chromosome 13 but not 7 causes an increase in tetraploidy due to cytokinesis failure.…”
Section: The Complex Relationship Between Aneuploidy and Chromosomal mentioning
confidence: 99%
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“…Thus, scWGS strongly supports that HeH ALL is chromosomally stable, in line with cytogenetic and SNP array data. Notably, this also shows that aneuploidy in cancer does not lead to CIN per se; something that has also been debated 33,34 .…”
Section: Discussionmentioning
confidence: 79%
“…Although we have not characterized the mechanism of the cell cycle arrest and/or delay that many CA-cells undergo, we note that previous findings by other groups showed that CA-cells divide aberrantly to generate aneuploidy at higher frequency than cells without extra centrioles ( Ganem et al. , 2009 ; Nicholson et al. , 2015 ) which can result in cell cycle arrest or cell death ( Nicholson et al.…”
Section: Resultsmentioning
confidence: 86%
“…, 2009 ; Nicholson et al. , 2015 ) which can result in cell cycle arrest or cell death ( Nicholson et al. , 2015 ),…”
Section: Resultsmentioning
confidence: 99%
“…Consistently, analysis in yeast has shown that aneuploid cells are less genomically stable and show increased rates of chromosome missegregation, mitotic recombination, and defective DNA damage repair (Sheltzer et al 2011;Zhu et al 2012). In human cells, specific aneuploidies have also been shown to increase mitotic error frequency (Nicholson et al 2015;Passerini et al 2016). In addition, while human cell lines with defined trisomies show reduced cell growth in vitro and in xenograft tumor assays, spontaneous karyotype evolution occurs during prolonged growth and improves cellular fitness (Sheltzer et al 2017).…”
Section: Aneuploidy Can Promote Further Genome Instabilitymentioning
confidence: 79%
“…In addition, aneuploidy can also generate karyotype-specific phenotypic changes that lead to mitotic defects. For example, trisomy of chromosome 13 results in a cytokinesis defect because of increased expression of a gene encoded on the aneuploid chromosome (Nicholson et al 2015). However, CIN is clearly not a necessary outcome of aneuploidy, as cells from individuals with specific trisomies exhibit rates of chromosome missegregation similar to those of euploid cells in vitro, and singlecell sequencing of neurons from an individual with Down syndrome failed to reveal additional aneuploidies (Valind et al 2013;van den Bos et al 2016).…”
Section: Aneuploidy Can Promote Further Genome Instabilitymentioning
confidence: 99%
“…This observation suggests that the advantage conferred by these two chromosomes may depend on a common phenotypic effect observed for both trisomies. Such an effect may be the increased rate of chromosome mis-segregation recently reported for DLD1 + 7, DLD1 + 13, and AF + 13 cells compared to diploid DLD1 and AF cells 27 . In DLD1 + 7, DLD1 + 13, and AF + 13 cells, high rates of chromosome mis-segregation are associated with high rates of karyotypic heterogeneity, which become apparent in the population even when cells are examined at relatively low passages 27 ; this is consistent with findings from other studies showing a link between aneuploidy and chromosome instability (CIN) in both yeast and human cells 39 41 43 44 45 46 .…”
Section: Discussionmentioning
confidence: 94%
“…Such an effect may be the increased rate of chromosome mis-segregation recently reported for DLD1 + 7, DLD1 + 13, and AF + 13 cells compared to diploid DLD1 and AF cells 27 . In DLD1 + 7, DLD1 + 13, and AF + 13 cells, high rates of chromosome mis-segregation are associated with high rates of karyotypic heterogeneity, which become apparent in the population even when cells are examined at relatively low passages 27 ; this is consistent with findings from other studies showing a link between aneuploidy and chromosome instability (CIN) in both yeast and human cells 39 41 43 44 45 46 . Cell populations with high rates of karyotypic heterogeneity are expected to display high degrees of phenotypic heterogeneity 33 47 and this karyotypic/phenotypic heterogeneity will allow aneuploid cells to be more “adaptable” 33 47 .…”
Section: Discussionmentioning
confidence: 94%
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