Ketomimetic nutrients remodel the glycocalyx and trigger a metabolic defense in breast cancer cells

• DOI: 10.1186/s40170-025-00385-3
• Publication Date: 2025-04-09T11:40:41Z
• Authors: Mohini Kamra; Yuan-I Chen; Paula C. Delgado; Erin H. Seeley; Stephanie K. Seid...; Hsin-Chih Yeh; Amy Brock; Sapun H. Parekh
• Keywords: Glycocalyx

While the triggers for metastatic transformation of breast cancer (BC) cells remain unknown, recent evidence suggests that intrinsic cellular metabolism could be a crucial driver migratory disposition and chemoresistance. Aiming to decipher molecular mechanisms involved in BC cell metabolic maneuvering, we study how ketomimetic (ketone body-rich, low glucose) nutrient medium can engineer glycocalyx signature cells, further maneuver their response therapy. Doxorubicin (DOX) has been used as model chemotherapeutic this study. Bioorthogonal imaging was assess degree sialylation along with measurements drug-induced cytotoxicity drug internalization. Single label-free performed, coupled measurement proliferative abilities, MS-based metabolomic screens. Transcriptomic analysis enzymes performed using total RNA extraction rt-qPCR. We found an inverse correlation internalization, where media enhanced protected from DOX. These hypersialylated proliferated slower migrated faster compared counterparts receiving high glucose media, while exhibiting preference glycolysis. also showed pronounced lipid droplet accumulation inversion profile. Enzymatic removal sialic acid moieties at revealed first time, direct role acids defense guards, blocking DOX entry membrane curtail Interestingly, non-cancerous mammary epithelial exhibited opposite trends differential pattern vs. normal traced its biochemical roots, i.e. expression levels key fatty synthesis. Our findings enhances chemoresistance invasive via two main oncogenic pathways: hypersialylation propose crosstalk between these pathways, juxtaposed synthesis glycan precursor UDP-GlcNAc, furthers advancement phenotype under conditions. Non-cancerous lack dual machinery end up being sensitized