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

XVII 胶原蛋白和半桥粒在基质驱动的胰腺癌进展和侵袭中的作用

• 批准号: 432470850
• 负责人: Dr. Louisa Bolm
• 金额: --
• 依托单位: Klinik für Chirurgie
• 依托单位国家: 德国
• 项目类别: Research Fellowships
• 财政年份: 2019
• 资助国家: 德国
• 起止时间: 2018-12-31 至 2021-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/432470850?language=en
• 关键词: role; Collagen; XVII; hemidesmosome; stroma; role; Collagen; XVII; hemidesmosome; stroma

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.

胰腺癌（PDAC）的特征是局部肿瘤的侵袭性和远处转移的早期形成。去胶质基质是PDAC的主要特征，癌细胞与基质成分之间的相互作用在肿瘤进展和癌细胞迁移中起重要作用。 PDAC脱粒基质含有大量的细胞外基质（ECM）以及与癌症相关的成纤维细胞（CAF）。 ECM和癌细胞之间通信的一种机制是通过半体体大体。半体体是蛋白质复合物，可作为基础膜和连接的上皮细胞之间的锚定。 Hemidesmosomes不仅介导细胞粘附，而且还可以作为将ECM连接到细胞中间细丝的信号传导复合物。胶原蛋白XVII是Hemidesmosmos的一部分，属于非成纤维形成的跨膜胶原的亚家族，既可以用作基质蛋白和细胞表面受体。宾客研究所（马萨诸塞州波士顿的马萨诸塞州综合医院外科胰腺研究实验室和哈佛医学院）的初步数据揭示了PDAC细胞和CAF之间的串扰，导致胶原蛋白XVII的上调。溴结构域和外交结构域（BET）蛋白是基质和PDAC细胞之间信号传导的主要决定因素。 BET家族形成了一组染色质衔接子，该适配器调节介导多种过程（例如细胞周期控制和炎症）的基因表达。这些蛋白会影响PDAC肿瘤ECM成分的调节。我们的假设是，半体体介导细胞与细胞外基质的通信，并激活PDAC癌细胞中促进肿瘤进展的信号通路。我们将进一步研究胶原蛋白XVII是否在PDAC生长中起作用并增加转移性扩散。我们期望通过与胶原蛋白XVII调节序列结合来鉴定介导胶原蛋白表达的BET蛋白。