|
| Status |
Public on Jan 15, 2018 |
| Title |
Chromosomal instability promotes metastasis through a cytosolic DNA response |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by high throughput sequencing
|
| Summary |
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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| Overall design |
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.
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| Contributor(s) |
Bakhoum S, Ngo B |
| Citation(s) |
29342134 |
| |
| Submission date |
Apr 25, 2017 |
| Last update date |
May 15, 2019 |
| Contact name |
Charles Murphy |
| E-mail(s) |
murphy.charlesj@gmail.com
|
| Organization name |
Weill Cornell Medicine
|
| Street address |
1300 York Ave
|
| City |
New York |
| State/province |
NY |
| ZIP/Postal code |
10065 |
| Country |
USA |
| |
|
| Platforms (2) |
| GPL16791 |
Illumina HiSeq 2500 (Homo sapiens) |
| GPL20301 |
Illumina HiSeq 4000 (Homo sapiens) |
|
| Samples (51)
|
|
| Relations |
| BioProject |
PRJNA384217 |
| SRA |
SRP105199 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE98183_Counts.geneSymbols.101bpSE.csv.gz |
508.1 Kb |
(ftp)(http) |
CSV |
| GSE98183_Counts.geneSymbols.75bpPE.csv.gz |
564.4 Kb |
(ftp)(http) |
CSV |
| GSE98183_FPKM.geneSymbols.101bpSE.csv.gz |
809.1 Kb |
(ftp)(http) |
CSV |
| GSE98183_FPKM.geneSymbols.75bpPE.csv.gz |
903.4 Kb |
(ftp)(http) |
CSV |
| GSE98183_VST.geneSymbols.101bpSE.csv.gz |
667.9 Kb |
(ftp)(http) |
CSV |
| GSE98183_VST.geneSymbols.75bpPE.csv.gz |
972.8 Kb |
(ftp)(http) |
CSV |
| GSE98183_counts.geneSymbols.csv.gz |
1.8 Mb |
(ftp)(http) |
CSV |
| GSE98183_fpkm.geneSymbols.csv.gz |
4.2 Mb |
(ftp)(http) |
CSV |
SRA Run Selector |
| Raw data are available in SRA |
| Processed data are available on Series record |
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