Cellular transformation promotes the incorporation of docosahexaenoic acid into the endolysosome-specific lipid bis(monoacylglycerol)phosphate in breast cancer

Bis(monoacylglycero)phosphates (BMPs), a class of lipids highly enriched within endolysosomal organelles, are key components of the lysosomal intraluminal vesicles responsible for activating sphingolipid catabolic enzymes. While BMPs are understudied relative to other phospholipids, recent reports associate BMP dysregulation with a variety of pathological states including neurodegenerative diseases and lysosomal storage disorders. Since the dramatic lysosomal remodeling characteristic of cellular transformation could impact BMP abundance and function, we employed untargeted lipidomics approaches to identify and quantify BMP species in several in vitro and in vivo models of breast cancer and comparative non-transformed cells and tissues. We observed lower BMP levels within transformed cells relative to normal cells, and consistent enrichment of docosahexaenoic acid (22:6) fatty acyl chain-containing BMP species in both human-and mouse-derived mammary tumorigenesis models. Our functional analysis points to a working model whereby 22:6 BMPs serve as reactive oxygen species scav-engers in tumor cells, protecting lysosomes from oxidant-induced lysosomal membrane permeabilization. Our findings suggest that breast tumor cells might divert polyunsaturated fatty acids into BMP lipids as part of an adaptive response to protect their lysosomes from elevated reactive oxygen species levels, and raise the possi-bility that BMP-mediated lysosomal protection is a tumor-specific vulnerability that may be exploited therapeutically.

Automated summary

Bis(monoacylglycero)phosphates (BMPs), lipid components within endolysosomal organelles, have been associated with pathological states such as neurodegenerative diseases and lysosomal storage disorders. This study identified lower BMP levels in transformed cells compared to normal cells, and observed an enrichment of 22:6 BMP species in breast cancer models. Functional analysis suggests that 22:6 BMPs serve as reactive oxygen species scavengers, protecting lysosomes from oxidant-induced damage. These findings highlight the potential therapeutic target of BMP-mediated lysosomal protection in breast tumor cells.