Chromosomal instability promotes metastasis through a cytosolic DNA response

Description: Summary from the GEO: " 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."

Overall Design from the GEO: " To determine whether CIN is causally involved in metastasis, we devised a genetic approach to alter the rate of chromosome missegregation in transplantable tumor models of human TNBC (MDA-MB-231);
cont: Control sample. Part of the CIN-medium group.
Ka; Overexpression of Kif2a, which does not affect the number of chromosome segregation errors during anaphase and serves as an additional control. Part of the CIN-medium group.
Kb; Overexpression of Kif2b, which leads to suppressed chromosome segregation errors during anaphase. Part of the CIN-low group.
MK; Overexpression of MCAK which leads to suppressed chromosome segregation errors during anaphase. Part of the CIN-low group.
MKH; Overexpression of dominant-negative form of MCAK, leading to increased number of chromosome segregation errors during anaphase. Part of the CIN-high group."

Subject of Study

Homo sapiens

Subject(s)

Chromosomal Instability

Chromosome Segregation

Cytosol

Membrane Proteins

NF-kappa B

Nucleotidyltransferases

Access via GEO
CSV files of RNA expression profiling by high throughput sequencing
Accession #: GSE98183

Access via SRA
RNA sequencing of 51 samples.
Accession #: SRP105199

Access via BioProject
Additional information about the overall inititative.
Accession #: PRJNA384217
Access Restrictions: Free to All
Access Instructions: The NCBI Gene Expression Omnibus, SRA, and BioProject databases provide open access to these files.
Associated Publications: Bakhoum S, Ngo B, Laughney A, et al. Chromosomal instability drives metastasis through a cytosolic DNA response. Nature. 2018; 553(7689):467-472.
Data Type: Genomic
Equipment Used: Illumina HiSeq 2500
High throughput sequencing system

Illumina HiSeq 4000
High throughput gene sequencing system
Software Used: SRA Toolkit
The NCBI SRA Toolkit enables reading ("dumping") of sequencing files from the SRA database and writing ("loading") files into the .sra format.
Dataset Format(s): CSV, SRA
Data Tool(s): RNA Seq
Dataset Size: 10.3 MB (CSV), 98.4 Gb (SRA)

Data Catalog Record Updated: 2023-12-07