Wim Steelant, PhD New Mexico Tech steelant@nmt.edu Phone:(505) 835-6778 Personal Website

Title: Glycosphingolipid Enriched Microdomains in Cancer Cell Invasion

Project Description:

The ultimate goal of this study is to investigate biological processes involving Glycosphingolipid Enriched Microdomains (GEM) and their implication in diseases, such as cancer. Understanding metastatic and invasive properties of tumor cells is crucial for the investigation of tumor malignancy. Any mechanism revealed could be a target for inhibition or prevention of tumor progression. Tumor cell malignancy can be characterized by organization of tumor-associated glycosphingolipid (GSL)-antigens in GEM, since they are involved in tumor cell adhesion and signal transduction. Recent studies have shown that monosialyl-Gb5 (MSGb5), a globo-series structure in GEM, organized with cSrc and FAK underlies the invasive properties of MCF-7 human breast cancer cells. ET-18-OMe (1-O-octadecyl-2-O-methyl-glycero-3-phosphocholine), an analog of the naturally occurring 2-lysophosphatidylcholine, belongs to a novel class of promising cancer chemotherapeutic drugs. Evidence showed that ET-18-OMe is able to influence invasion in MCF-7 cells. Our preliminary data indicate that ET-18-OMe alters the invasive properties of MCF-7 cells due to a change in composition and localization of GEM. The delicate balance between an invasion promoter episialin (MUC1) and invasion suppressor E-cadherin is disturbed due to ET-18-OMe-induced clustering. In addition, ET-18-OMe-induced translocation has been previously reported in human leukemia cells, causing apoptosis through clustering and translocation of Fas/CD95 into GEM, however the mechanism remains to be established. We will therefore investigate the change in composition and translocation of GEM with the involvement of MUC1, E-cadherin, MSGb5 and signal transducers as cSrc, and FAK in the mechanism underlying ET-18-OMe induced invasion. Cell and tissue-culture will be used to study invasion into collagen and chick heart, while activation of signaling pathways will be elucidated by means of inhibitors of protein-phosphorylation in Western blot analysis. In collaboration with the University of New Mexico, GEM translocation will be visualized using confocal microscopy. Long-term objectives of this project involve studying (i) glycosphingolipid composition, (ii) signal transducers and (iii) membrane receptors in vivo.