DNA damage contributes to cGAS-STING activation in colon cancer
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA691757 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR13426557_1.fastq.gz | Fastqsanger.gz | |||
| SRR13426557_2.fastq.gz | Fastqsanger.gz | |||
| SRR13426558_1.fastq.gz | Fastqsanger.gz | |||
| SRR13426558_2.fastq.gz | Fastqsanger.gz | |||
| SRR13426559_1.fastq.gz | Fastqsanger.gz |
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Project description:This study aimed to investigate the role of DNA damage contributes in STING pathway activation and its implication in colorectal cancer.
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Project description:Colorectal cancer is the second leading cause of cancer mortality in the US. Although immune checkpoint blockade therapies such as anti-PD-1/PD-L1 have had successes in some patients, the response rate is still low. We have found that riluzole, a well-tolerated FDA-approved oral medicine for treating amyotrophic lateral sclerosis, increased intratumoral CD8+ T cells and suppressed tumor growth of colon cancer cells in syngeneic immune competent mice. Riluzole-mediated tumor suppression was dependent on the presence of CD8+ T cells. Riluzole activates the cytosolic DNA sensing cGAS/STING pathway and increases expression of interferon β (IFNβ) and IFNβ-regulated genes including CXCL10. Inhibition of ATM, but not ATR, results in a synergistic increase in IFNβ expression, suggesting that riluzole-dependent double strand breaks contribute to cGAS/STING activation. Knockout of cGAS or STING significantly attenuated expression of IFNβ and CXCL10 and nearly abolished suppression of tumor growth. Riluzole failed to increase intratumoral CD8+ T cells in STING knockout tumors. These results indicate that riluzole recruits CD8+ T cells into the tumor microenvironment through tumor cell intrinsic STING activation. When riluzole was combined with a PD-1 antibody, the treatment was more effective in suppressing tumor growth in vivo. Taken together, our studies indicate that riluzole inhibits tumor growth through the activation of cGAS/STING signaling and may increase the efficacy of anti-PD-1/PD-L1 therapies in colon cancer.
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Project description:Aging is a major risk factor for cardiovascular diseases and the accumulation of DNA damage significantly contributes to the aging process. This study aimed to identify the underlying molecular mechanisms of vascular aging in DNA-repair-deficient progeroid Ercc1Δ/- mice and to explore the therapeutic effect of dietary restriction (DR). RNA sequencing analysis revealed that DR reversed gene expression of vascular aging processes including extracellular matrix remodeling in the Ercc1Δ/- aorta. Notably, this analysis indicated the presence of macrophage-like vascular smooth muscle cells (VSMCs) and suggested cGAS-STING pathway activation. The presence of macrophage-like VSMCs and increased STING1 expression were confirmed in Ercc1Δ/- aortic tissue and were both reduced by DR. In vitro, cisplatin-induced DNA damage activated the cGAS-STING pathway in Ercc1Δ/- VSMCs but not in wildtype VSMCs. These findings identify involvement of the cGAS-STING pathway in DNA damage driven vascular aging and underscore the therapeutic benefits of DR for vascular aging. Furthermore, upstream regulator analysis revealed compounds that may replicate the beneficial effects of DR, providing promising leads for further investigation.
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