GLYCOSPHINGOLIPID ENRICHED MICRODOMAINS IN CANCER CELL INVASION

这个子项目是许多利用 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 鞘糖脂富集微区与癌细胞侵袭 本研究的最终目标是研究涉及鞘糖脂富集微区（GEM）的生物学过程及其在疾病（如癌症）中的意义。癌细胞侵袭是一个高度复杂的多步骤过程，其特征在于细胞粘附分子的表达水平改变和蛋白水解酶的分泌，沿着多种细胞蛋白在多个分支信号通路中的表达或活性的变化。此外，质膜含有富含肿瘤相关鞘糖脂（GSL）-抗原的膜微区，其作为细胞粘附的介质，并在信号传导分子中，为细胞信号传导提供重要的位置。最近的研究表明，肿瘤细胞的侵袭往往是由于GSL和/或膜蛋白的差异组织和聚集以及它们与信号分子的组装所引发的异常信号机制。合成的醚脂质类似物ET-18-OMe（1-O-十八烷基-2-O-甲基-甘油-3-磷酸胆碱）先前显示出影响人乳腺癌和结肠癌细胞的侵袭，并用作诱导细胞侵袭的分子探针，以探索关键分子的组成、易位和组织的变化以及膜微区的可能参与。 我们的研究结果表明，重组，集群和特定的膜蛋白和信号转导与鞘糖脂在膜微区的组装负责细胞-细胞粘附的损失，并随后导致MCF-7乳腺癌细胞的侵袭力增加。相反，HCT-8结肠癌细胞的侵袭行为是通过整合素α 1亚基的聚集和相关FAK/cSrc复合物的激活而启动的。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Glycosphingolipid Enriched Microdomains in Cancer Cell Invasion The ultimate goal of this study was to investigate biological processes involving Glycosphingolipid Enriched Microdomains (GEM) and their implication in diseases, such as cancer. Cancer cell invasion is a highly complex and multistep process, that is characterized by altered expression levels of cell adhesion molecules and secretion of proteolytic enzymes, along with changes in expression or activities of a variety of cellular proteins in multiple branching signaling pathways. In addition, the plasma membrane contains membrane microdomains enriched in tumor-associated glycosphingolipid (GSL)-antigens that function as mediators of cell adhesion, and in signaling molecules, providing important locations for cell signaling. Recent studies showed that tumor cell invasion often results from aberrant signaling mechanisms initiated by differential organization and clustering of GSLs and/or membrane proteins, and their assembly with signaling molecules. The synthetic ether lipid analog ET-18-OMe (1-O-octadecyl-2-O-methyl-glycero-3-phosphocholine) was previously shown to influence invasion of human breast and colon cancer cells and is used as a molecular probe to induce cellular invasion in order to explore changes in composition, translocation and organization of crucial molecules and the possible involvement of membrane microdomains. Our results show that reorganization, clustering and assembly of specific membrane proteins and signal transducers with glycosphingolipids in membrane microdomains are responsible for loss of cell-cell adhesion and subsequent result in increased invasiveness of MCF-7 breast cancer cells. In contrast, the invasive behavior of HCT-8 colon cancer cells was initiated through clustering of integrin alpha1 subunits and the activation of associated FAK/cSrc complexes.