Dynamic Shifts in ER-Plasma Membrane Junctions Signaling Define Pro-Metastatic N-Glycosylation and Predict Prostate...

Area of Science:

• Oncology
• Cell Biology
• Glycobiology

Background:

• Prostate cancer (PCa) poses a significant global health challenge, with current screening lacking precision for aggressive forms.
• Tissue-based biomarkers are crucial for distinguishing aggressive PCa, necessitating research into metastatic mechanisms.
• Existing knowledge links Golgi disorganization, ER stress, and high-mannose glycoproteins to metastatic PCa, but their interplay is unclear.

Purpose of the Study:

• To investigate the relationship between Golgi disorganization, ER stress, and high-mannose glycoproteins in prostate cancer metastasis.
• To explore the role of ER-plasma membrane (PM) junctions, mediated by STIM1 and ORP5, in PCa progression and metastasis.
• To identify potential new biomarkers for aggressive PCa.

Main Methods:

• Comparative analysis of primary and metastatic prostate tumor cells.
• Investigation of endoplasmic reticulum (ER)-plasma membrane (PM) junction dynamics involving STIM1 and ORP5.
• Glycan analysis focusing on high-mannose and MGAT5-modified sugars.
• Assessment of Golgi structure and Integrin αv clustering.

Main Results:

• Primary PCa growth correlates with increased ER-PM junctions (STIM1/ORP5).
• Metastasis involves downregulation of ER-PM junctions, Golgi dispersal, and conversion of high-Man glycans to MGAT5-modified sugars.
• MGAT5-modified glycans facilitate Integrin αv clustering via Galectin-3, promoting metastasis.
• Golgi dispersal increases organelle surface area for heightened trafficking.

Conclusions:

• STIM1 and ORP5 are potential biomarkers for aggressive PCa.
• High-mannose enrichment in PCa reflects active cancer cell utilization, not defective maturation.
• The ER stress response in PCa should encompass Golgi reorganization and altered ER-PM junctions.