Dynamic Shifts in ER–Plasma Membrane Junctions Signaling Define Pro‐Metastatic N‐Glycosylation and Predict Prostate Cancer Progression

ABSTRACT Prostate cancer (PCa) is the second most common and a leading cause of cancer‐related deaths among men. Current screening methods lack precision in distinguishing aggressive cases, emphasizing a need for tissue‐based biomarkers. Although Golgi disorganization, ER stress, and elevated high‐mannose (Man) glycoproteins (e.g., Integrin α v , key metastatic player) are recognized features of metastatic prostate tumors, their interrelationships remain unexplored. It is observed that the growth of primary prostate tumors is linked to an increase in endoplasmic reticulum (ER)–plasma membrane (PM) junctions signaling, mediated by STIM1 and ORP5. However, transition to lymph node and tissue metastasis is associated with their downregulation, loss of ER–PM communications, significant Golgi dispersal, and rapid conversion of high‐Man glycans in the Golgi to atypical MGAT5‐modified sugars that facilitate Integrin α v clustering at the PM via Galectin‐3 binding. Golgi dispersal is associated with increased organelle volume and surface area to accommodate heightened trafficking and processing. These findings position STIM1 and ORP5 as biomarkers of aggressive PCa and show that high‐Man enrichment is not due to defective maturation but reflects a glycan pool that cancer cells actively utilize, suggesting that the concept of ER stress response in PCa should be redefined to include Golgi reorganization and altered ER–PM junctions.