The role of Collagen XVII and the hemidesmosome in stroma-driven progression and invasiveness of pancreatic cancer

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Pancreatic cancer (PDAC) is characterized by aggressive local tumor growth and early formation of distant metastases. Desmoplastic stroma is a main feature of PDAC and interaction between cancer cells and stromal components play an important role in tumor progression and cancer cell migration. PDAC desmoplastic stroma contains high amounts of extracellular matrix (ECM) as well as cancer-associated fibroblasts (CAF). One mechanism of communication between ECM and cancer cells is through hemidesmosomes. Hemidesmosomes are protein complexes acting as an anchor between the basal membrane and the connected epithelial cells. Hemidesmosomes not only mediate cell adhesion, but also serve as signaling complex connecting ECM to the intermediate filaments of cells. Collagen XVII is part of the hemidesmosome and belongs to the subfamily of non-fibril-forming transmembrane collagens functioning as both matrix proteins and cell surface receptors. Preliminary data from the guest institute (Pancreatic Research Laboratory, Department of Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, USA) have revealed the crosstalk between PDAC cells and CAFs to result in an upregulation of Collagen XVII. Bromodomain and extraterminal domain (BET) proteins are major determinants of signaling between stroma and PDAC cells. The BET family form a group of chromatin adaptors that regulate gene expression mediating multiple processes such as cell cycle control and inflammation. These proteins impact the regulation of ECM components of PDAC tumors. Our hypothesis is that hemidesmosomes mediate cell communication with the extracellular matrix and activate signaling pathways within PDAC cancer cells promoting tumor progression. We will further examine if Collagen XVII plays a role in PDAC growth and increased metastatic spread. We expect to identify BET-proteins mediating Collagen XVII expression via binding to Collagen XVII regulatory sequences.