Fig. 6: A proposed model of the role of PDIA1 and PDIA1-enriched EVs in bladder cancer cell survival and disease recurrence.

Within both and non-transformed cells, PDIA1 transitions between oxidized (PDIA1^oxi) and reduced (PDIA1^red) states as it catalyzes disulfide bond formation and isomerization for misfolded and unfolded proteins in the ER. This activity is engaged at elevated levels under conditions of ER stress that arise in bladder cancer cells, triggering the generation of large quantities of H₂O₂ as a byproduct of this process. Tumor cells release large quantities of primarily oxidized PDIA1 in their EVs, mitigating this oxidative stress in a manner conducive to cell survival. These bladder tumor cell-derived EVs, in turn, can deliver PDIA1 to recipient non-transformed urothelial cells, wherein it can generate elevated levels of H₂O₂ that, over time, triggers DNA damage contributing to a higher risk of malignant transformation that may contribute to the development of recurrent lesions.