Malignant transformation-induced alterations in bis(monoacylglycerol)phosphate (BMP)

Bis(monoacylglycero)phosphates (BMP), a lipid class highly enriched within endolysosomal organelles, fulfills critical roles in lysosome function and stability. BMPs are required for proper formation of intraluminal lysosomal structures, preserving membrane integrity by facilitating the activation of lipid metabolizing enzymes. While BMPs are largely understudied in comparison to other phospholipid classes, recent reports associate BMP dysregulation with a variety of pathological states including neurodegenerative diseases and lysosomal storage disorders. Considering that the lysosome is extensively remodeled in the process of malignant transformation, we sought to investigate BMP alterations in cancer. In this study, we identified and quantified BMP species across in vitro and in vivo models of breast cancer and comparative non-transformed cells and tissues and report striking cancer-selective changes in overall BMP abundance and molecular composition. Specifically, we observed a consistent enrichment of 22:6 fatty acyl chain-containing BMP species in both human- and mouse-derived mammary tumorigenesis models, suggesting a distinct biological role for BMP in transformation. Indeed, functional analyses uncovered a potential role for 22:6 BMPs as reactive oxygen species scavengers in tumor cells, which exhibit elevated basal levels of oxidant stress relative to non-transformed cells. Our findings reveal the molecular diversity of BMP lipids in breast tumor and non-transformed tissue models, and contribute to a growing body of evidence implicating BMPs in physiological and disease processes.