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

胰腺癌（PDAC）的特点是局部肿瘤的侵袭性生长和远处转移的早期形成。结缔组织增生是PDAC的主要特征，癌细胞与基质组分的相互作用在肿瘤进展和癌细胞迁移中起着重要作用。PDAC间质含有大量的细胞外基质（ECM）和癌症相关成纤维细胞（CAF）。ECM和癌细胞之间的一种通讯机制是通过半脂质体。半粒酶是一种蛋白质复合物，在基膜和连接的上皮细胞之间起锚定作用。半粒酶体不仅介导细胞黏附，而且是连接ECM与细胞中间丝的信号复合物。XVII胶原是半脂体的一部分，属于非原纤维形成的跨膜胶原亚家族，同时作为基质蛋白和细胞表面受体。来自客座研究所（马萨诸塞州总医院外科胰腺研究实验室和哈佛医学院，波士顿，美国）的初步数据显示PDAC细胞和CAFs之间的串扰导致胶原XVII的上调。溴结构域和外结构域（BET）蛋白是间质细胞和PDAC细胞之间信号传导的主要决定因素。BET家族形成一组染色质接头，调节基因表达介导多种过程，如细胞周期控制和炎症。这些蛋白影响PDAC肿瘤的ECM成分的调节。我们的假设是半粒体介导细胞与细胞外基质的通信，并激活PDAC癌细胞内的信号通路，促进肿瘤进展。我们将进一步研究胶原XVII是否在PDAC生长和转移性扩散中起作用。我们期望通过结合胶原XVII调节序列来鉴定介导胶原XVII表达的bet蛋白。

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.