Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Transient genomic instability drives tumorigenesis through accelerated clonal evolution

ABSTRACT: Abnormal numerical and structural chromosome content is frequently found in human cancer. However, the role of aneuploidy in tumor initiation and progression is poorly understood. To test the effect of aneuploidy on cancer development, we transiently induced chromosome instability (CIN) in mice by inducible overexpression of polo-like kinase 4 (PLK4), a master regulator of centrosome number. Short term increased PLK4 expression generated significant centrosome amplification and aneuploidy resulting in the formation of aggressive T cell lymphomas in mice with heterozygous inactivation of one p53 allele or accelerated tumor development in the absence of p53. Transient CIN increased the frequency of lymphoma-initiating cells, as revealed by T cell receptor sequencing of tumor samples. Transient CIN produced a unique tumor karyotype containing triploid chromosomes 4, 5, 14, and 15, as determined by whole genome sequencing.

ORGANISM(S): Mus musculus

PROVIDER: GSE161728 | GEO | 2021/06/14

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Shared Molecules

Only show the datasets with similarity scores above: 0.5

Threshold

0.5

Similar Datasets

Centrosome amplification triggers tumorigenesis in p53 deficient epidermis

Project description:While aneuploidy is found in more than 90% of solid tumors, it is unclear whether aneuploidy is the cause or the consequence of tumorigenesis. Different mouse models deficient in centrosomal or spindle checkpoint proteins that induce aneuploidy show either a promotion or a decrease in tumorigenesis depending on the tissues and the types of oncogenic stimuli. To investigate the effects of aneuploidy in skin development and tumorigenesis, we used Plk4 over-expression (Plk4OE) during epidermal development to assess centrosome amplification and aneuploidy. We found that PLK4OE in the developing epidermis induced centrosome amplification and multipolar divisions, consequently led to p53 stabilization and apoptosis of epidermal progenitors. This delayed epidermal stratification and induced lethal skin barrier defect in 50% of the mice. Plk4 transgene expression was shutdown postnatally in the surviving mice and PLK4OE mice never developed spontaneous skin tumors. Concomitant Plk4OE and P53 deletion (PLK4OE/p53cKO) rescued the defects in differentiation and stratification. Unexpectedly, p53 deletion did not rescue the apoptosis or eventual elimination of the cells overexpressing PLK4 and presenting multiple centrosomes. Remarkably, the short term presence of cells with supernumerary centrosomes postnatally was sufficient to generate aneuploidy and triggered spontaneous skin cancers with complete penetrance. These results reveal for the first time that aneuploidy induced by centrosome amplification, even if transient, can trigger tumorigenesis.

2015-10-27 | E-MTAB-3733 | biostudies-arrayexpress

Mapping karyotypic heterogeneity in chromosomal instable murine T-cell acute lymphoblastic lymphomas using single-cell sequencing

Project description:Chromosome instability (CIN) leads to aneuploidy and copy number variations (CNVs). Even though both are hallmarks of cancer cells, aneuploidy inhibits proliferation of untransformed cells, suggesting that cancer cells have adapted to cope with CIN. The spindle assembly checkpoint (SAC) prevents CIN by monitoring chromosome attachment and sister chromatid tension in mitosis. By conditionally inactivating Mad2, an essential SAC gene, we find that SAC inactivation in T-cells or hepatocytes is remarkably well tolerated and becomes tumorigenic when placed in a p53null or p53+/- predisposed background. The resulting T-ALLs and HCCs are highly aneuploid, exhibit clonal copy number changes that are tumor specific despite ongoing CIN, indicating that CIN is a powerful driver of tumor evolution.

2017-03-20 | GSE63688 | GEO

Chromosome copy number changes in Mad2-null-driven p53 null HCC and T-ALL samples

Project description:Mad2 and p53 loss were combined in liver or T-cells specificely leading to early onset and highly aggressive aneuploid HCC and T-ALL. Tumours were characterized for (recurrrent) copy number changes with a focus on whole chromosome abnormalities. DNA content was compared to the DNA content of sex-matched uninfiltrated control liver samples from litter mates Chromosome instability (CIN) leads to aneuploidy and copy number variations (CNVs). Even though both are hallmarks of cancer cells, aneuploidy inhibits proliferation of untransformed cells, suggesting that cancer cells have adapted to cope with CIN. The spindle assembly checkpoint (SAC) prevents CIN by monitoring chromosome attachment and sister chromatid tension in mitosis. By conditionally inactivating Mad2, an essential SAC gene, we find that SAC inactivation in T-cells or hepatocytes is remarkably well tolerated and becomes tumorigenic when placed in a p53null or p53+/- predisposed background. The resulting T-ALLs and HCCs are highly aneuploid, exhibit clonal copy number changes that are tumor specific despite ongoing CIN, indicating that CIN is a powerful driver of tumor evolution.

2017-03-20 | GSE63686 | GEO

Transcriptomes of aneuploid mouse liver tumors and T-ALL

Project description:Transcriptome analysis to map transcriptomes of Mad2 p53null-driven aneuploid liver cancers and T-ALLs, to determine correlation between copy number changes and expression changes and to map the transcriptional response to CIN Chromosome instability (CIN) leads to aneuploidy and copy number variations (CNVs). Even though both are hallmarks of cancer cells, aneuploidy inhibits proliferation of untransformed cells, suggesting that cancer cells have adapted to cope with CIN. The spindle assembly checkpoint (SAC) prevents CIN by monitoring chromosome attachment and sister chromatid tension in mitosis. By conditionally inactivating Mad2, an essential SAC gene, we find that SAC inactivation in T-cells or hepatocytes is remarkably well tolerated and becomes tumorigenic when placed in a p53null or p53+/- predisposed background. The resulting T-ALLs and HCCs are highly aneuploid, exhibit clonal copy number changes that are tumor specific despite ongoing CIN, indicating that CIN is a powerful driver of tumor evolution.

2017-03-20 | GSE63687 | GEO

Gene expression analysis of MTBTOM tumors

Project description:Tumors that overexpress the MYC oncogene frequently demonstrate aneuploidy, numerical chromosome alterations associated with highly aggressive cancers, rapid tumor evolution, and poor patient outcome. Here, we identify that MYC overexpression induces defects in microtubule nucleation and mitotic spindle assembly, promoting chromosome segregation defects, micronuclei and chromosomal instability (CIN). High TPX2 expression is permissive for mitotic spindle assembly and chromosome segregation in cells with MYC overexpression; whereas TPX2 depletion blocks mitotic progression, induces cell death and prevents tumor growth. Attenuating MYC expression reverses mitotic defects, even in established tumor cell lines, implicating an ongoing role for high MYC in the persistence of CIN in tumors. Our studies implicate the MYC oncogene as a regulator of spindle assembly and identify a new MYC-TPX2 synthetic-lethal interaction that could represent a future therapeutic strategy in MYC-overexpressing cancers. Moreover, our studies suggest that blocking MYC activity can attenuate the emergence of CIN and tumor evolution.

2020-03-30 | GSE130921 | GEO

Gene expression analysis of EuMyc lymphoma cells after MYC inactivation

2020-03-30 | GSE130920 | GEO

Down-regulation of Polo-like kinase 4 (PLK4) induces G1 arrest via activation of the p38/p53/p21 signalling pathway in bladder

Project description:We demonstrate that Polo-like kinase 4(PLK4) is overexpressed in human bladder cancer (BC) cell lines and tissues, and its overexpression correlates with poor prognosis. PLK4 inhibition suppresses BC cell growth and induces G1 phase arrest via activating p38/p53/p21 pathway in vitro and in vivo. The data suggest that PLK4 might serve as a novel molecular target for BC treatment.

2021-07-29 | GSE180958 | GEO

Use of the Polo-like kinase 4 (PLK4) inhibitor centrinone to investigate intracellular signaling networks using SILAC-based phosphoproteomics_C4PR

Project description:Polo-like kinase 4 (PLK4) is the master regulator of centriole duplication in metazoan organisms. Catalytic activity and protein turnover of PLK4 are tightly coupled in human cells, since changes in PLK4 concentration and catalysis have profound effects on centriole duplication and supernumerary centrosomes, which are associated with aneuploidy and cancer. Recently, PLK4 has been targeted with a variety of small molecule kinase inhibitors exemplified by centrinone, which induces inhibitory effects on PLK4 and can lead to on-target centrosome depletion. Despite this, relatively few PLK4 substrates have been identified unequivocally in human cells, and the extent of PLK4 signalling remains poorly characterised. We report an unbiased mass spectrometry-based quantitative analysis of cellular protein phosphorylation in stable PLK4-expressing human cells exposed to the small molecule inhibitor centrinone. PLK4 phosphorylation was itself sensitive to brief exposure to centrinone, resulting in PLK4 stabilization. A drug-resistant PLK4 mutant (G95R) confirmed several on-target effects of the compound towards PLK4. Using this experimental system, we report hundreds of centrinone-regulated phosphoproteins in U2OS cells, including centrosomal and cell cycle proteins and a variety of likely non cell-cycle substrates. Surprisingly, sequence interrogation of ~300 significantly downregulated phosphoproteins reveals an extensive network of centrinone-sensitive [Ser/Thr]Pro phosphorylation target sequence motifs, which based on our analysis might be either direct or indirect targets of PLK4. In addition, we confirm NMYC and PTPN12 as new PLK4 substrates, both in vitro and in human cells. Our findings suggest that PLK4 catalytic output directly controls the phosphorylation of a diverse set of cellular proteins, including Pro-directed targets that are likely to be important in PLK4-mediated cell signalling.

2021-06-14 | PXD018704 | Pride

The Impact of Monosomies, Trisomies and Segmental aneuploidies on Chromosomal stability

Project description:Aneuploidy and chromosomal instability are both commonly found in cancer. Chromosomal instability leads to karyotype heterogeneity in tumors and is associated with therapy resistance, metastasis and poor prognosis. It has been hypothesized that aneuploidy per se is sufficient to drive CIN, however due to limited models and heterogenous results, it has remained controversial which aspects of aneuploidy can drive CIN. In this study we systematically tested the impact of different types of aneuploidies on the induction of CIN. We generated a plethora of isogenic aneuploid clones harboring whole chromosome or segmental aneuploidies in human p53-deficient RPE-1 cells. We observed increased segregation errors in cells harboring trisomies that strongly correlated to the number of gained genes. Strikingly, we found that clones harboring only monosomies do not induce a CIN phenotype. Finally, we found that an initial chromosome breakage event and subsequent fusion can instigate breakage-fusion-bridge cycles. By investigating the impact of monosomies, trisomies and segmental aneuploidies on chromosomal instability we further deciphered the complex relationship between aneuploidy and CIN.

2022-06-14 | GSE193437 | GEO

Re-replication generates whole-chromosomal instability and anueploidy

Project description:Aneuploidy, a hallmark of cancer, often arises from whole-chromosomal instability (W-CIN). Many cancers exhibiting W-CIN, however, show no direct insult to the mitotic proteins that ensure proper segregation of chromosomes. This has stimulated interest in identifying defects in non-mitotic processes that might disrupt chromosome behavior in mitosis. Here we show in Saccharomyces cerevisiae that transient re-replication of centromeric DNA, due to deregulation of replication initiation proteins, greatly induces aneuploidy of the rereplicated chromosome. Some of this aneuploidy appears to arise from simple missegregation of both sister chromatids to one daughter cell, indicating that centromeric re-replication can disrupt proper centromere function during mitosis. Another source of aneuploidy appears to be the generation of an extra sister chromatid via homologous recombination, suggesting that centromeric rereplication can trigger breakage and repair events that expand chromosome numbers while preserving chromosome structure. Given the emerging connections between the deregulation of replication initiation proteins and oncogenesis, our findings offer the possibility of a new non-mitotic source of aneuploidy that may be relevant to cancer.

2014-07-25 | GSE55641 | GEO

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data