β8 Integrin Mediates Pancreatic Cancer Cell Radiochemoresistance.
Sha JinWei-Chun LeeDaniela AustChristian PilarskyNils CordesPublished in: Molecular cancer research : MCR (2019)
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.
Keyphrases
- single cell
- cell therapy
- extracellular matrix
- high throughput
- squamous cell carcinoma
- signaling pathway
- cell adhesion
- radiation therapy
- cell death
- dna methylation
- risk assessment
- papillary thyroid
- machine learning
- ejection fraction
- pseudomonas aeruginosa
- cell proliferation
- artificial intelligence
- binding protein
- small molecule
- amino acid
- big data
- patient reported outcomes
- induced apoptosis
- replacement therapy