Lipid rafts are dynamic, cholesterol-rich membrane micro-domains that regulate molecular interactions. Many tumor suppressors and oncogenes localize to lipid rafts, including the tumor suppressor, opioid binding protein cell adhesion molecule (OPCML), which is frequently inactivated in epithelial ovarian cancer. Since OPCML is an extracellular GPI-anchored protein with no cytoplasmic domains, we hypothesized that it acts by modulating lipid raft composition. To dissect raft-mediated mechanism of tumor suppressor effect of OPCML in ovarian cancer, and compare with other cancer raft proteomics studies, subcellular quantitative proteomics coupled with network analysis was performed on ovarian cancer SKOV3 cells expressing OPCML wild type or partially active P95R mutant. RaftProt database was used for comparative analysis with other cancer rafts. Enrichment and interaction network analysis revealed altered lipid raft-cytoskeleton interaction upon expression of OPCML. Interestingly, wild type but not P95R OPCML significantly increased vimentin and desmin in lipid rafts. Independent meta-analysis of 3 lipid raft proteomics datasets modeling progression in breast cancer, renal cell carcinoma and melanoma showed that over half of the commonly-altered lipid raft proteins were cytoskeleton associated. Taken together, these results suggest enhanced cytoskeletal-membrane raft interaction as a common feature of aggressive progression in tumors.