Chromosome mis-segregation and cytokinesis failure in trisomic human cells

Nicholson, Joshua M.; Macedo, Joana Catarina; Mattingly, Aaron; Wangsa, Darawalee; Camps, Jordi; Lima, Vera; Gomes, Ana Margarida; Dória, Sofia; Ried, Thomas; Logarinho, Elsa; Cimini, Daniela

doi:10.7554/elife.05068

Cited by 95 publications

(99 citation statements)

References 74 publications

(125 reference statements)

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“…One possibility that we are currently exploring is that this reflects an adaptive response to loss of p38α function during the clonal expansion following the CRISPR/Cas9 process. Another possibility is that aneuploidy induced by loss of p38 may predispose cells to cytokinesis failure, a phenomenon described in trisomic DLD-1 cells ( Nicholson et al., 2015 ). Nevertheless, it raises the possibility that post-mitotic survival of p38α null cells is a consequence of avoiding aneuploidy by becoming tetraploid.…”

Section: Discussionmentioning

confidence: 99%

The p38α Stress Kinase Suppresses Aneuploidy Tolerance by Inhibiting Hif-1α

et al. 2018

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SummaryDeviating from the normal karyotype dramatically changes gene dosage, in turn decreasing the robustness of biological networks. Consequently, aneuploidy is poorly tolerated by normal somatic cells and acts as a barrier to transformation. Paradoxically, however, karyotype heterogeneity drives tumor evolution and the emergence of therapeutic drug resistance. To better understand how cancer cells tolerate aneuploidy, we focused on the p38 stress response kinase. We show here that p38-deficient cells upregulate glycolysis and avoid post-mitotic apoptosis, leading to the emergence of aneuploid subclones. We also show that p38 deficiency upregulates the hypoxia-inducible transcription factor Hif-1α and that inhibiting Hif-1α restores apoptosis in p38-deficent cells. Because hypoxia and aneuploidy are both barriers to tumor progression, the ability of Hif-1α to promote cell survival following chromosome missegregation raises the possibility that aneuploidy tolerance coevolves with adaptation to hypoxia.

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“…It is now generally accepted that CIN and aneuploidy are fundamental forces driving carcinogenesis (23). Additionally, aneuploidy per se has been shown to promote chromosome missegregation in both yeast (24,25) and mammalian cells (26,27). Also, tetraploidy has been proposed as a possible precursor of aneuploidy in cancer (2).…”

Section: Discussionmentioning

confidence: 99%

Near‐tetraploid cancer cells show chromosome instability triggered by replication stress and exhibit enhanced invasiveness

et al. 2018

Self Cite

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A considerable proportion of tumors exhibit aneuploid karyotypes, likely resulting from the progressive loss of chromosomes after whole-genome duplication. Here, by using isogenic diploid and near-tetraploid (4N) single-cell-derived clones from the same parental cell lines, we aimed at exploring how polyploidization affects cellular functions and how tetraploidy generates chromosome instability. Gene expression profiling in 4N clones revealed a significant enrichment of transcripts involved in cell cycle and DNA replication. Increased levels of replication stress in 4N cells resulted in DNA damage, impaired proliferation caused by a cell cycle delay during S phase, and higher sensitivity to S phase checkpoint inhibitors. In fact, increased levels of replication stress were also observed in nontransformed, proliferative posttetraploid RPE1 cells. Additionally, replication stress promoted higher levels of intercellular genomic heterogeneity and ongoing genomic instability, which could be explained by high rates of mitotic defects, and was alleviated by the supplementation of exogenous nucleosides. Finally, our data found that 4N cancer cells displayed increased migratory and invasive capacity, both in vitro and in primary colorectal tumors, indicating that tetraploidy can promote aggressive cancer cell behavior.-Wangsa, D., Quintanilla, I., Torabi, K., Vila-Casadesús, M., Ercilla, A., Klus, G., Yuce, Z., Galofré, C., Cuatrecasas, M., Lozano, J. J., Agell, N., Cimini, D., Castells, A., Ried, T., Camps, J. Near-tetraploid cancer cells show chromosome instability triggered by replication stress and exhibit enhanced invasiveness.

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“…This phenomenon is associated with an increase in the concentration of the spartin protein, which is localized in centrosomes and microtubules during mitosis. The SPG20 gene encoding this protein is located on chromosome 13 28 .…”

Section: Discussionmentioning

confidence: 99%

Identification of differentially methylated genes in first-trimester placentas with trisomy 16

Tolmacheva

Vasilyev

Nikitina

et al. 2022

Sci Rep

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The presence of an extra chromosome in the embryo karyotype often dramatically affects the fate of pregnancy. Trisomy 16 is the most common aneuploidy in first-trimester miscarriages. The present study identified changes in DNA methylation in chorionic villi of miscarriages with trisomy 16. Ninety-seven differentially methylated sites in 91 genes were identified (false discovery rate (FDR) < 0.05 and Δβ > 0.15) using DNA methylation arrays. Most of the differentially methylated genes encoded secreted proteins, signaling peptides, and receptors with disulfide bonds. Subsequent analysis using targeted bisulfite massive parallel sequencing showed hypermethylation of the promoters of specific genes in miscarriages with trisomy 16 but not miscarriages with other aneuploidies. Some of the genes were responsible for the development of the placenta and embryo (GATA3-AS1, TRPV6, SCL13A4, and CALCB) and the formation of the mitotic spindle (ANKRD53). Hypermethylation of GATA3-AS1 was associated with reduced expression of GATA3 protein in chorionic villi of miscarriages with trisomy 16. Aberrant hypermethylation of genes may lead to a decrease in expression, impaired trophoblast differentiation and invasion, mitotic disorders, chromosomal mosaicism and karyotype self-correction via trisomy rescue mechanisms.

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“…At first glance, this result contradicts with experimentally observed increased missegregation of various aneuploid karyotypes (Ganem et al, 2009; Lengauer et al, 1997; Thompson and Compton, 2008). Although missegregation of aneuploid karyotype is generally increased, different aneuploid karyotypes are characterized by various missegregation rates (Hintzen et al, 2021; Nicholson et al, 2015b). Our theoretical result, in combination with these experimental findings, suggests that those cells with lower missegregation will be selected among different aneuploid karyotypes.…”

Section: Discussionmentioning

confidence: 99%

“…One of key processes which drives karyotype evolution is chromosome missegregation, which is increased for many tumor karyotypes and termed chromosome instability (CIN) (Hintzen et al, 2021; Nicholson & Cimini, 2013; Thompson & Compton, 2008). Missegregation includes gain or loss of one or a few chromosomes due to incorrect attachment of chromosomes to the mitotic spindle (Bakhoum et al, 2009; Cimini, 2008; Dewhurst et al, 2014; Nicholson et al, 2015; Thompson & Compton, 2011b). Another key process for karyotype evolution is cell proliferation, which determines how the total number of cells with a certain karyotype changes over time.…”

Section: Introductionmentioning

confidence: 99%

Proliferative advantage of specific aneuploid cells drives evolution of tumor karyotypes

Ban

Tomašić

Trakala

et al. 2022

Preprint

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Most tumors have abnormal karyotypes, which arise from mistakes during mitotic division of healthy euploid cells and evolve through numerous complex mechanisms. In a recent mouse model with high levels of chromosome missegregation, chromosome gains dominate over losses both in pretumor and tumor tissues, whereas tumors are characterized by gains of chromosomes 14 and 15. However, the mechanisms driving clonal selection leading to tumor karyotype evolution remain unclear. Here we show, by introducing a mathematical model based on a concept of a macro-karyotype, that tumor karyotypes can be explained by proliferation-driven evolution of aneuploid cells. In pretumor cells, increased apoptosis and slower proliferation of cells with monosomies lead to predominant chromosome gains over losses. Tumor karyotypes with gain of one chromosome can be explained by karyotype-dependent proliferation, while for those with two chromosomes an interplay with karyotype-dependent apoptosis is an additional possible pathway. Thus, evolution of tumor-specific karyotypes requires proliferative advantage of specific aneuploid karyotypes.

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“…At first glance, this result contradicts experimentally observed increased missegregation of various aneuploid karyotypes ( 11 , 39 , 40 ). Although missegregation of aneuploid karyotype is generally increased, different aneuploid karyotypes are characterized by various missegregation rates ( 27 , 29 ). Our theoretical result, in combination with these experimental findings, suggests that those cells with lower missegregation will be selected among different aneuploid karyotypes.…”

Section: Discussionmentioning

confidence: 99%

“…One of key processes that drives karyotype evolution is chromosome missegregation, which is increased for many tumor karyotypes and termed chromosome instability (CIN) ( 11 , 26 , 27 ). Missegregation includes gain or loss of one or a few chromosomes due to incorrect attachment of chromosomes to the mitotic spindle ( 9 , 28 , 29 , 30 , 31 ). Another key process for karyotype evolution is cell proliferation, which determines how the total number of cells with a certain karyotype changes over time.…”

Section: Introductionmentioning

confidence: 99%

Proliferative advantage of specific aneuploid cells drives evolution of tumor karyotypes

Ban¹,

Tomašić²,

Trakala³

et al. 2023

Biophysical Journal

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“…More ambiguously, the RAB18-interacting microtubule-binding proteins have not previously been reported to work together but do function in compatible locations. SPG20 and CAMSAP1 each associate with mitotic spindle poles, REEP4 participates in spindle-dependent ER clearance from metaphase chromatin, and BICD2 is a component of the minus-end-directed dynein–dynactin motor complex ( 67 , 68 , 69 , 70 , 71 , 72 , 73 ). Our TRAPPII-dependent RAB18 interaction data indicate that different GEF complexes affect largely distinct subsets of interactions.…”

Section: Discussionmentioning

confidence: 99%

Comparative proximity biotinylation implicates the small GTPase RAB18 in sterol mobilization and biosynthesis

Kiss,

Chicoine,

Khalil

et al. 2023

Journal of Biological Chemistry

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“…Our results limit the range within which erroneous attachments are efficiently eliminated between approximately 80% and 180% (approximately −0.1 and 0.25 respectively, on a base 10 logarithmic scale) of the Aurora A expression level used to reproduce the oscillation observed in normal cells. Despite these values are merely a stipulation of what the real range could be, our model suggests that Aurora A inhibition as well as its upregulation, like the condition observed in cancer cells (Ertych et al, 2014;He et al, 2014;Nicholson et al, 2015;Kao et al, 2017), leads to deficient erroneous attachment correction, and consequently to chromosome missegregation and CIN. Although further considerations and new parameters will fade the gap between simulation and reality, our model provides a framework to understand the relevance of Aurora A expression level on the error correction mechanism and chromosome dynamics.…”

Section: Uni-dimensional and Bi-dimensional Interpretationmentioning

confidence: 90%

A mathematical model of kinetochore-microtubule attachment regulated by Aurora A activity gradient describes chromosome oscillation and correction of erroneous attachments

et al. 2021

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Chromosome oscillation during metaphase is attenuated in cancer cell lines, concomitant with the reduction of Aurora A activity on kinetochores, which results in reduced mitotic fidelity. To verify the correlation between Aurora A activity, chromosome oscillation, and error correction efficiency, we developed a mathematical model of kinetochore-microtubule dynamics, based on stochastic attachment/detachment events regulated by Aurora A activity gradient centered at spindle poles. The model accurately reproduced the oscillatory movements of chromosomes, which were suppressed not only when Aurora A activity was inhibited, but also when it was upregulated, mimicking the situation in cancer cells. Our simulation also predicted efficient correction of erroneous attachments through chromosome oscillation, which was hampered by both inhibition and upregulation of Aurora A activity. Our model provides a framework to understand the physiological role of chromosome oscillation in the correction of erroneous attachments that is intrinsically related to Aurora A activity. Recently, we reported that inefficient error correction through chromosome oscillation may underlie CIN in cancer cell lines (Iemura et al., 2021). Chro-

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“…"In agreement with previous work (Nicholson et al, 2015), the trisomic clones showed similar aberrations, albeit to a lesser extent (Supplemental Figure S2B). "…”

Section: Citation Statement Classification Explanationmentioning

(Expert classified)

“…Such enriched citation information is more informative than a traditional citation index. For example, when Viganó et al (2018) cites Nicholson et al (2015), traditional citation indices report this citation by displaying the title of the citing paper and other bibliographic information such as the journal, year published, and other metadata .…”

Section: Introductionmentioning

confidence: 99%

scite: A smart citation index that displays the context of citations and classifies their intent using deep learning

Nicholson¹,

Mordaunt²,

Lopez³

et al. 2021

Quantitative Science Studies

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Citation indices are tools used by the academic community for research and research evaluation which aggregate scientific literature output and measure impact by collating citation counts. Citation indices help measure the interconnections between scientific papers but fall short because they fail to communicate contextual information about a citation. The usage of citations in research evaluation without consideration of context can be problematic, because a citation that presents contrasting evidence to a paper is treated the same as a citation that presents supporting evidence. To solve this problem, we have used machine learning, traditional document ingestion methods, and a network of researchers to develop a “smart citation index” called scite, which categorizes citations based on context. Scite shows how a citation was used by displaying the surrounding textual context from the citing paper and a classification from our deep learning model that indicates whether the statement provides supporting or contrasting evidence for a referenced work, or simply mentions it. Scite has been developed by analyzing over 25 million full-text scientific articles and currently has a database of more than 880 million classified citation statements. Here we describe how scite works and how it can be used to further research and research evaluation. Peer Review https://publons.com/publon/10.1162/qss_a_00146

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“…Also, human cells with extra chromosomes were shown to have replicative defects because of down-regulation of the helicase, MCM2-7, and importantly, these aneuploid cells were found to be genomically unstable (Passerini et al, 2016). Similar experiments on trisomic colorectal cancer cells also show that these aneuploid cells mis-segregate chromosomes at a higher rate than the control diploids (Nicholson et al, 2015).…”

Section: Introductionmentioning

confidence: 89%

Whole chromosome loss and associated breakage–fusion–bridge cycles transform mouse tetraploid cells

et al. 2017

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Whole chromosome gains or losses (aneuploidy) are a hallmark of ~70% of human tumors. Modeling the consequences of aneuploidy has relied on perturbing spindle assembly checkpoint (SAC) components, but interpretations of these experiments are clouded by the multiple functions of these proteins. Here, we used a Cre recombinase-mediated chromosome loss strategy to individually delete mouse chromosomes 9, 10, 12, or 14 in tetraploid immortalized murine embryonic fibroblasts. This methodology also involves the generation of a dicentric chromosome intermediate, which subsequently undergoes a series of breakage-fusion-bridge (BFB) cycles. While the aneuploid cells generally display a growth disadvantage , they grow significantly better in low adherence sphere-forming conditions and three of the four lines are transformed, forming large and invasive tumors in immunocompromised mice. The aneuploid cells display increased chromosomal instability and DNA damage, a mutator phenotype associated with tumorigenesis Thus, these studies demonstrate a causative role for whole chromosome loss and the associated BFB-mediated instability in tumorigenesis and may shed light on the early consequences of aneuploidy in mammalian cells.

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“…Frozen hMSCs P9 previously cultured along four passages in FBS, frozen hMSCs P9 previously cultured along four passages in SCC + bFGF + TGFβ1 on Fn and frozen hMSCs P4 (input cells) were quickly thawed in superfrost ultra plus slides (Thermo Scientific, Life Technologies, CA, USA) and cultured for 24 hr. FISH analysis of interphase nuclei was performed as previously described (Nicholson et al, ).…”

Section: Methodsmentioning

confidence: 99%

Optimization of the use of a pharmaceutical grade xeno‐free medium for in vitro expansion of human mesenchymal stem/stromal cells

Cimino

Gonçalves

Bauman

et al. 2017

J Tissue Eng Regen Med

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Human bone marrow-derived mesenchymal stem/stromal cells (hMSCs) are considered promising therapeutic agents in the field of cell therapy and regenerative medicine, mainly due to their relative facility to be isolated, multi-differentiation potential, and immunomodulatory role. However, their application in clinics requires a crucial step of in vitro expansion. Most of the protocols for hMSCs in vitro culture use foetal bovine serum as medium supplement that, being from animal origin, presents several safety concerns and may initiate xenogeneic immune responses after cells transplantation. This work reports the optimization of a pharmaceutical-grade xeno-free strategy for hMSCs in vitro expansion based on the supplementation of basal medium with a pharmaceutical-grade human plasma-derived supplement for cell culture (SCC) and 2 human growth factors (bFGF and TGFβ1), plus a coating of human plasma fibronectin (Fn). After 4 weeks in culture, this strategy improves hMSCs expansion yield about 4.3-fold in comparison with foetal bovine serum supplementation and 4.5-fold compared with a commercially available xeno-free medium. hMSCs expanded in SCC-based formulation maintained their phenotype and differentiation capacity into osteogenic, adipogenic, and chondrogenic lineages, without alterations in cell karyotype. Overall, the SCC-based medium appears to be an excellent alternative for the xeno-free expansion of hMSCs as therapeutic agents for clinical applications.

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Chromosome mis-segregation and cytokinesis failure in trisomic human cells

Cited by 95 publications

References 74 publications

The p38α Stress Kinase Suppresses Aneuploidy Tolerance by Inhibiting Hif-1α

Near‐tetraploid cancer cells show chromosome instability triggered by replication stress and exhibit enhanced invasiveness

Identification of differentially methylated genes in first-trimester placentas with trisomy 16

Proliferative advantage of specific aneuploid cells drives evolution of tumor karyotypes

Proliferative advantage of specific aneuploid cells drives evolution of tumor karyotypes

Comparative proximity biotinylation implicates the small GTPase RAB18 in sterol mobilization and biosynthesis

A mathematical model of kinetochore-microtubule attachment regulated by Aurora A activity gradient describes chromosome oscillation and correction of erroneous attachments

scite: A smart citation index that displays the context of citations and classifies their intent using deep learning

Whole chromosome loss and associated breakage–fusion–bridge cycles transform mouse tetraploid cells

Optimization of the use of a pharmaceutical grade xeno‐free medium for in vitro expansion of human mesenchymal stem/stromal cells

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