Cell biological characterization of EBAG9/RCAS1 as a modifier of tumor-associated O-linked glycan expression

异常的糖链表位被认为是基本上所有类型的实验性和人类癌症的标志。O连锁血型前体结构Tf(Thomsen-Friedenreich)和Tn受到特别关注，因为它们通常是隐蔽的，而且它们发生在各种肿瘤细胞上。它们是O-葡聚糖合成不完全的结果，并被糖链延伸和唾液酸化封闭在免疫系统之外。在功能上，转铁蛋白和转铁蛋白被认为与肿瘤细胞的黏附、侵袭和转移有关。导致它们在肿瘤中发生的机制仍然知之甚少。我们最近鉴定了一种肿瘤相关抗原EBAG9，它导致TN和TF在细胞系上沉积。SNARE相关分子Snapin作为相互作用伙伴的鉴定表明，EBAG9参与了分泌途径的控制。在这里，我们将应用多学科方法来研究EBAG9相关的O-连接多糖表达的途径和功能后果。我们将测试这一假说，EBAG9是否在调节不同的囊泡运输途径中具有更普遍的作用，以及这一功能是否可以在肿瘤发病机制和某些肿瘤实体中EBAG9表达的放松调控之间提供联系。总之，这项应用旨在开发囊泡运输、O-连接多糖合成和肿瘤发病机制的综合概念框架。

Aberrant glycan epitopes are appreciated as a hallmark of essentially all types of experimental and human cancers. The O-linked blood group precursor structures TF (Thomsen-Friedenreich) and Tn have received particular attention because they are normally cryptic and they occur on a variety of tumor cells. They result from incomplete O-glycan synthesis and are occluded from the immune system by glycan extension and sialylation. Functionally, TF and Tn are thought to be involved in tumor cell adhesion, invasion, and metastasis. The mechanisms that contribute to their occurrence in tumors remain poorly understood. We have recently characterized a tumor-associated antigen, EBAG9, which caused the deposition of Tn and TF on cell lines. The identification of the SNAREassociated molecule Snapin as an interaction partner pointed to an involvement of EBAG9 in the control of the secretory pathway. Here, we will apply a multidisciplinary approach to study the pathways and functional consequences of EBAG9-related O-linked glycan expression. We will test the hypothesis if EBAG9 has a more general role in the regulation of diverse vesicle trafficking routes and if this function can provide a link between tumor pathogenesis and deregulation of EBAG9 expression in some tumor entities. In conclusion, this application is aimed at the development of an integrated conceptual framework for vesicle transport, O-linked glycan synthesis, and tumor pathogenesis.