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 controls cancer cell survival, proliferation and therapy resistance. Here, we identified β8 integrin in a high-throughput knockdown screen in three-dimensional (3D), ECM-based cell cultures for novel focal adhesion protein targets as critical determinant of PDAC cell radiochemoresistance. Intriguingly, β8 integrin localizes with the golgi apparatus perinuclearly in PDAC cells and resection specimen from PDAC patients. Upon radiogenic genotoxic injury, β8 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 β8 integrin to autophagy, which is diminished in the absence of β8 integrin. Collectively, our data reveal β8 integrin to critically co-regulate PDAC cell radiochemoresistance, intracellular vesicle trafficking and autophagy upon irradiation.