The Caspase-Activated DNAse drives chromosomal instability and cancer metastasis

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. Overall design: Total RNA was isolated from ctrl, CAD deficient, STING deficient, or zVAD treated Hela 229 and MDA-MB-231 cell lines. 4 riplicates were used for "Sequencing"