The human immune system exhibits both specific and non-specific immunity (innate immunity) to defend against pathogens. The cGAS/STING pathway plays an essential role in innate immunity by sensing cytoplasmic DNA derived from viral or bacterial infection, and damaged genomic or mitochondrial DNA. Evading immune destruction is a hallmark of cancer, and loss of STING in certain cancers promotes immune- resistance. Interestingly, cGAS has been found to promote cellular senescence, and low cGAS expression correlates with poor outcome in lung cancer. However, whether and how cGAS inactivation is critical for tumorigenesis, and whether cGAS exerts any innate immunity-independent functions in cancer remain elusive. Breast cancer constitutes 25% of all cancers in women, making it the most common malignancy in females. Metastatic disease, rather than primary tumors, causes most death in breast cancer patients, and there is currently no effective therapeutic options available for this deadly disease. Understanding the molecular mechanisms governing breast cancer metastasis may lead to development of therapeutic interventions to target an ?Achilles? heel? this disease. Here we provide several lines of evidence to indicate that nuclear cGAS exerts a novel function, which is independent of its canonical function in innate immunity, in suppressing breast cancer metastasis. First, we observed levels of nuclear cGAS decreased in metastatic, compared with primary breast cancer. Second, we found that acetylation of cGAS in its NLS (nuclear localization signal) promoted cGAS nuclear enrichment and that loss of nuclear cGAS promoted breast cancer metastasis. Third, we identified cGAS as a novel H4K8me1 reader which functions to suppress metastatic gene expression. As a result, deficiency in H4K8me1 binding significantly facilitated breast cancer metastasis. Given that our informatics analyses in TCGA breast cancer patients indicated that total cGAS expression did not correlate with metastasis nor disease stage, we will further determine whether reduced cGAS acetylation (that correlates with reduced nuclear cGAS levels) can be used as a prognostic marker for metastatic breast cancer using a cohort of primary and metastatic breast cancer patient samples readily available. In addition, we will examine the molecular mechanisms and biological consequences underlying the metastasis suppressive function of cGAS using both xenograft and genetic murine models, along with the initial exploration of therapeutic vulnerabilities associated with this dysregulated pathway. Overall, our studies have significant implications for metastatic breast cancer, along with new potential insights relative to breast cancer recurrence. We are hopeful that our studies will facilitate the development of new therapeutic options for breast cancer patients, with potential relevance to a subset of lung cancer as well.
Metastatic breast cancer is a deadly disease with no effective cure to date. This proposal aims to elucidate a novel function for nuclear cGAS in suppressing metastatic gene expression independent of its canonical function in innate immunity. We will also examine whether cGAS acetylation is a critical regulation to promote cGAS nuclear enrichment and whether inhibiting the major cGAS deacetylase could be used as a new avenue of therapeutic intervention for metastatic breast cancer.