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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

基本信息

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

项目摘要

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)以局部侵袭性生长和早期形成远处转移为特征。促结缔组织间质是PDAC的主要特征，癌细胞与间质成分之间的相互作用在肿瘤的进展和癌细胞的迁移中起着重要作用。PDAC促结缔组织间质含有大量的细胞外基质(ECM)和癌相关成纤维细胞(CAF)。细胞外基质和癌细胞之间的一种通讯机制是通过半桥粒。半桥粒是在基底膜和相连的上皮细胞之间起锚作用的蛋白质复合体。半桥粒不仅介导细胞黏附，而且作为连接细胞外基质和细胞中间丝的信号复合体。XVI型胶原是半桥粒的一部分，属于非纤维形成的跨膜胶原亚家族，具有基质蛋白和细胞表面受体的双重功能。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美国波士顿哈佛医学院)的初步数据显示，PDAC细胞和CAF之间的串扰导致XVII胶原蛋白表达上调。溴结构域和端外结构域(BET)蛋白是基质和PDAC细胞之间信号传递的主要决定因素。BET家族形成一组染色质适配子，调节基因表达，介导细胞周期控制和炎症等多个过程。这些蛋白质影响PDAC肿瘤细胞外基质成分的调节。我们的假设是，半桥粒介导细胞与细胞外基质的通讯，并激活PDAC癌细胞内的信号通路，促进肿瘤进展。我们将进一步研究是否胶原XVII在PDAC生长和增加转移扩散中起作用。我们希望通过与XVII胶原蛋白调控序列的结合来鉴定介导XVII胶原蛋白表达的BET蛋白。