The Caspase-Activated DNAse drives chromosomal instability and cancer metastasis
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA649945 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR12360056_1.fastq.gz | Fastqsanger.gz | |||
| SRR12360056_2.fastq.gz | Fastqsanger.gz | |||
| SRR12360057_1.fastq.gz | Fastqsanger.gz | |||
| SRR12360057_2.fastq.gz | Fastqsanger.gz | |||
| SRR12360058_1.fastq.gz | Fastqsanger.gz |
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Project description:Chromosome-segregation errors in cancer cells are linked to chromosomal instability, the appearance of micronuclei and subsequent intracellular signaling events that drive cancer metastasis. The cause of these aberrations is not well-defined but a link to DNA-damage has been established. The Caspase-Activated DNAse (CAD) has been discovered for its role in the degradation of DNA in apoptotic cells but can also be activated in the absence of cell death. We here show that spontaneous CAD-activity drives chromosome missegregation, micronuclei generation, invasive growth and metastasis in human cancer cells. Genomic deletion of CAD reduced chromosome missegregation in mouse intestinal organoids as well as in tumor cells. CAD-deficient human cancer cells showed reduced migration, invasion and anchorage-independent growth in vitro as well as reduced metastatic potential in zebrafish and in mice. CAD-deficient cells displayed a substantially altered gene-expression profile, which overlapped with the profile of cells deficient in the Stimulator of Interferon Genes (STING). Multiple cancer signaling pathways were found to be regulated by CAD. A CAD-associated gene expression signature strongly predicted poor survival in cancer patients. These results identify CAD as a regulator of a signaling programme that determines cancer progression and prognosis.
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Project description:Hoxa13 overexpression drives chromosomal instability and liver tumorigenesis in mice
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Project description:Background and aims: Class I Homeobox (HOX) genes are fundamental components of embryonic patterning and morphogenesis, also implicated in neoplastic transformations. Among them HOXA13, in particular, has been found to be the most overexpressed in HCC and to be associated with worse prognosis. However, no previous work has shown so far a direct causal effect between HOXA13 overexpression and liver tumorigenesis. In this study we aimed to prove the direct oncogenicity of HOXA13 in the liver and to unravel the molecular mechanisms of Hoxa13-induced liver tumorigenesis. Approach and Results: To unravel the oncogenic mechanism of HOXA13 in vivo, a transgenic mouse model of HOXA13 overexpression in the liver was generated using hydrodynamic tail vein injection coupled with a transposase system. The mice phenotype was followed over time, from 2 weeks up to 1-year post injection. RNA-sequencing was performed to monitor the transcriptomic changes over time. HOXA13-overexpression in the liver led to highly proliferative hepatocytes and correlated with the DNA damage marker yH2AX. 1-year post-injection 50% of the injected mice developed liver tumors of various histological grades and types. RNA-sequencing analysis performed on whole liver extracts of 2 weeks-old mice and tumors showed that the main pathway deregulated by HOXA13 overexpression was cell cycle, in particular G2/M transition and mitotic spindle assembly checkpoint. Additionally, HOXA13-overexpressing livers showed a transcriptomic signature of chromosomal Instability, suggesting a possible mechanism of tumorigenesis driven by genome instability. Conclusions: Our study highlights the role of HOXA13 as a novel oncogenic driver in hepatocarcinogenesis and strongly suggests that its oncogenic properties are least partially mediated by induction of chromosomal instability.
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Project description:Chromosomal instability is a hallmark of cancer that results from ongoing errors in chromosome segregation during mitosis. Although chromosomal instability is a major driver of tumour evolution, its role in metastasis has not been established. Here we show that chromosomal instability promotes metastasis by sustaining a tumour cell-autonomous response to cytosolic DNA. Errors in chromosome segregation create a preponderance of micronuclei whose rupture spills genomic DNA into the cytosol. This leads to the activation of the cGAS-STING (cyclic GMP-AMP synthase-stimulator of interferon genes) cytosolic DNA-sensing pathway and downstream noncanonical NF-κB signalling. Genetic suppression of chromosomal instability markedly delays metastasis even in highly aneuploid tumour models, whereas continuous chromosome segregation errors promote cellular invasion and metastasis in a STING-dependent manner. By subverting lethal epithelial responses to cytosolic DNA, chromosomally unstable tumour cells co-opt chronic activation of innate immune pathways to spread to distant organs.
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Project description:Chromosomal instability (CIN) is a hallmark of cancer, and it results from ongoing errors in chromosome segregation during mitosis. While CIN is a major driver of tumor evolution, its role in metastasis has not been established. Here we show that CIN promotes metastasis by sustaining a tumor-cell autonomous inflammatory response to cytosolic DNA. Errors in chromosome segregation create a preponderance of micronuclei whose envelopes frequently rupture exposing their DNA content to the cytosol. This leads to the activation of the cGAS-STING cytosolic DNA-sensing pathway and downstream noncanonical NF-kB signaling. Genetic suppression of CIN significantly delays metastasis in transplantable tumor models, whereas inducing chromosome segregation errors promotes cellular invasion and metastasis in a STING-dependent manner. In contrast to primary tumors, human and mouse metastases strongly select for CIN, in part, due to its ability to enrich for metastasis-initiating mesenchymal subpopulations, offering an opportunity to target chromosome segregation errors for therapeutic benefit.
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Project description:We explored the role of CCAT2 in inducing chromosomal instability in gastrointestinal cancers.
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Project description:Chromosomal instability (CIN), an ongoing rate of chromosome missegregation during mitosis, is a defining feature of cancer. However, high chromosomal aberrations are detrimental for cell fitness. Here we investigated mechanisms allowing lethal prostate cancer (PCa) to tolerate and survive increasing CIN. Transcriptomic and proteomic analysis of patient datasets and experimental models showed a concomitant increase of CIN and cell division fidelity kinases in lethal PCa. Functional studies identified MASTL as a key kinase to which therapy-resistant PCa cells become addicted to restrain lethal CIN and ensure survival. Combined analysis of transcription factors increased in high CIN PCa patient datasets with detailed promoter analysis identified that MASTL expression is regulated by the Androgen Receptor variant 7 (AR-V7) and E2F7. Finally, targeting MASTL addiction vulnerability in vivo using the small molecule inhibitor GKI-1, improves survival of pre-clinical models. These findings provide proof-of-concept for exploiting CIN levels as a therapeutic approach in cancer.
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Project description:TP53 loss initiates chromosomal instability in fallopian tube epithelial cells
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Project description:Chromosomal instability (CIN) is a known hallmark of cancer, yet it also imposes stresses that reduce cellular fitness. In order to bridge the gap in knowledge on how cancer cells adapt to CIN-imposed stresses, we performed genome-wide transposon mutagenesis screen. Samples deposited in this database were acquired from mice used in our in vivo mutagenesis screen.
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Project description:Background and Aims: Telomere dysfunction can increase tumor initiation by induction of chromosomal instability, but initiated tumor cells need to reactivate telomerase for genome stabilization and tumor progression. However, this concept has not been proven in vivo since appropriate mouse models were lacking. Here, we analyzed hepatocarcinogenesis (i) in a novel mouse model of inducible telomere dysfunction on a telomerase-proficient background, (ii) in telomerase knockout mice with chronic telomere dysfunction (G3 mTerc-/-), and (iii) in wild-type mice with functional telomeres and telomerase. Transient or chronic telomere dysfunction enhanced the rates of chromosomal aberrations during hepatocarcinogenesis, but only telomerase-proficient mice exhibited significantly increased rates of macroscopic tumor formation and cancer cell proliferation in response to telomere dysfunction. In contrast, telomere dysfunction resulted in pronounced accumulation of DNA damage, cell cycle arrest and apoptosis in telomerase-deficient liver tumors. Together, these data provide the first in vivo evidence that transient telomere dysfunction during early and late stages of tumorigenesis can promote chromosomal instability and carcinogenesis in telomerase-proficient mice in the absence of additional genetic checkpoint defects at germline level.
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