Cytoplasmic DNA sequencing of colorectal cancer samples
Genomic instability is a driver of colorectal cancer onset and progression and can be caused either by endogenous loss of DNA repair functions (such as loss of DNA mismatch repair) or DNA-damaging therapies (such as radiation or 5-fluorouracil). Genomic instability increases release of DNA from the nucleus into the cytosol of colorectal cancer cells and this can stimulate endogenous DNA-sensing pathways that evolved to detect viral infection. This activates type I IFN-related genes that play a critical role in stimulating antitumor immunity. Cytosolic DNA from genomically unstable cells may thus inform design of new treatments that therapeutically stimulate a similar immune response without the risks associated with increasing genomic instability in cancer cells. This project sequenced cytosolic DNA from colorectal cancer cells with disruption in different DNA repair pathways and that were treated or not with DNA-damaging therapies. The goal was to determine if there are specific sequences associated with different types of genomic instability and whether these sequences can be correlated with the intensity of antitumor immunity they stimulate. DNA with similar sequences could thus be formulated into adjuvant therapies that stimulate immune responses against colorectal cancers.