Abstract

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.

Highlights

  • Pancreatic ductal adenocarcinoma (PDAC) is one of the five most lethal malignancies in the world

  • We explored the function of b8 integrin in PDAC therapy resistance and unraveled parts of its contributing molecular mechanism

  • Parts of the protein interactome of b8 integrin facilitate a connection to autophagy, which is diminished in the absence of b8 integrin

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Summary

Introduction

Pancreatic ductal adenocarcinoma (PDAC) is one of the five most lethal malignancies in the world. One putative cancer target in PDAC is the PDAC cell/ extracellular matrix (ECM) interaction as PDACs are stromarich tumors [4]. This stroma consists of numerous ECM components such as collagens, laminins, fibronectin, and hyaluronic acid [5]. Cells interact with ECM components via cell adhesion receptors that coalesce with receptor tyrosine kinases, adapter and signaling molecules to form focal adhesion complexes These membranous multiprotein complexes are essentially coregulating key cell functions such as survival, cell death, proliferation, metastasis, and therapeutic resistance [6, 7]. We explored the function of b8 integrin in PDAC therapy resistance and unraveled parts of its contributing molecular mechanism. Parts of the protein interactome of b8 integrin facilitate a connection to autophagy, which is diminished in the absence of b8 integrin

Materials and Methods
Results
Gy X-rays esi RNA control esi β8 integrin
Discussion
Gy X-rays esi RNA control esi integrin β8 esi RNA control esi integrin β8
Disclosure of Potential Conflicts of Interest
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