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 β8
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, 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 coregulate PDAC cell radiochemoresistance, intracellular vesicle trafficking, and autophagy upon irradiation. IMPLICATIONS: This study identified β8
integrin as an essential determinant of PDAC cell radiochemosensitivity and as a novel potential
cancer target.