β8 Integrin Mediates Pancreatic Cancer Cell Radiochemoresistance

Pancreatic ductal adenocarcinoma (PDAC) stroma, composed of extracellular matrix (ECM) proteins, promotes therapy resistance and poor survival rate. Integrin-mediated cell/ECM interactions are well known to control cancer cell survival, proliferation, and therapy resistance. Here, we identified beta 8 integrin in a high-throughput knockdown screen in three-dimensional (3D), ECM-based cell cultures for novel focal adhesion protein targets as a critical determinant of PDAC cell radiochemoresistance. Intriguingly, beta 8 integrin localizes with the golgi apparatus perinuclearly in PDAC cells and resection specimen from PDAC patients. Upon radiogenic genotoxic injury, beta 8 integrin shows a microtubule-dependent perinuclear-to-cytoplasmic shift as well as strong changes in its proteomic interactome regarding the cell functions transport, catalysis, and binding. Parts of this interactome link beta 8 integrin to autophagy, which is diminished in the absence of beta 8 integrin. Collectively, our data reveal beta 8 integrin to critically coregulate PDAC cell radiochemoresistance, intracellular vesicle trafficking, and autophagy upon irradiation.