UC San Diego

Cancer cells frequently carry chromosomal abnormalities, called aneuploidy. Aneuploidy has been reported to have association with impaired immune response in tumors. Various studies focus on investigating aneuploidy in cancer to gain insights into potential therapeutics for cancer. Endoplasmic reticulum (ER) stress, which is as prevalent as aneuploidy in tumor cells, has also been suggested to have potential impact on immune surveillance during tumor progression. We have experimentally validated that drug induced aneuploidy in vitro leads to an increase of ER stress in cells, which will then initiate the unfolded protein response (UPR). In this thesis we provide a new perspective, investigating ER stress as the potential mechanism by which aneuploidy helps tumor cells escape from immune response during progression. We confirmed the activation signal from 3 branches of UPR and among which, PERK remained universally unperturbed across 31 cancer types. The activity of PERK downstream transcription factor, EIF2Α and DDIT3, were highly correlated with aneuploidy level, suggesting cross talk between the PERK branch pathway and aneuploidy state. Partial correlation testing and linear models were applied to confirm the immune-suppressive function of EIF2α and DDIT3. These results support that the PERK pathway could potentially be a new therapeutic target in cancer treatment.