Computational Lipidomics Reveals Environment-Specific Membrane Remodeling in Prostate Cancer

Metabolic changes during cancer progression produce key differences in phospholipid distributions among normal (RWPE-1), benign hyperplasia (BPH-1), and metastatic prostate (lymph: LNCaP, bone: PC-3, and brain: DU145) cell lines that are markers of disease progression and cancer cell adaptation (Young et al., 2021). The effect of cancer-associated lipidome shifts on membrane structural dynamics has not been investigated in a cell-specific context. Here, we spatially map the specific membrane lipidome from each cell line data set to assess membrane organization and dynamics in normal, benign hyperplasia, and metastatic prostate cell lines. Long time scale molecular dynamics simulations show leaflet-specific alterations in membrane dynamics, with increased fluidity in the intracellular leaflet of metastatic membranes. All membranes exhibited phase-separated domains enriched in polyunsaturated lipids and depleted in cholesterol; however, the extent of phase separation varied with disease state. Specifically, the loss of phosphatidylserine lipid leaflet asymmetry in metastatic cell membranes decreased the level of phospholipid phase separation. In particular, the metastatic LNCaP lymph node cell line showed exaggerated phase separation for distinct phospholipid species compared to all other metastatic and noncancerous lines. These alterations in lipid colocalization and phase separation patterns across prostate cancer cell membrane lines suggest environment-specific adaptations that may play a role in cancer progression.