Protein disulfide isomerase-enriched extracellular vesicles from bladder cancer cells support tumor survival and malignant transformation in the bladder.

Bladder cancer (BC) patients face high rates of disease recurrence, partially driven by the cancer field effect. This effect is mediated in part by the release of pro-tumorigenic cargos in membrane-enclosed extracellular vesicles (EVs), but the specific underlying mechanisms remain poorly understood. Protein disulfide isomerase (PDIA1) catalyze disulfide bond formation and can help mitigate endoplasmic reticulum (ER) stress, potentially supporting tumor survival. Here, BC cells were found to exhibit better survival under ER stress when PDIA1 was downregulated. These cells maintained homeostatic PDIA1 levels through the EV-mediated release of PDIA1. Chronic exposure of urothelial cells to these PDIA1-enriched BCEVs induced oxidative stress and DNA damage, ultimately leading to the malignant transformation of recipient cells. The EV-transformed cells exhibited DNA damage patterns potentially attributable to oxidative damage, and PDIA1 was found to be a key tumorigenic cargo within EVs. Tissue microarray analyses of BC recurrence confirmed a significant correlation between tumor recurrence and the levels of both PDIA1 and ER stress. Together, these data suggest that cancer cells selectively sort oxidized PDIA1 into EVs for removal, and these EVs can, in turn, induce oxidative stress in recipient urothelial cells, predisposing them to malignant transformation and thereby increasing the risk of recurrence.