MULTI-OMICS PROFILING DECODES BACE2-DEPENDENT METABOLIC REWIRING IN METASTATIC MELANOMA

BACE2 has traditionally been studied in the context of neurodegenerative diseases. However, its involvement in cancer progression has become increasingly recognized. While in melanocytes, BACE2 physiologically cleaves the PMEL protein to generate peptides that form the melanin scaffold, our group recently demonstrated that, in metastatic melanoma, BACE2 activity is deregulated and amyloid-like fibrils are secreted, altering tumor microenvironment stiffness and promoting invasive features. While investigating BACE2 role in cancer, we identified a deregulation of lipid-related enzymes. Given that metastatic melanoma is characterized by high metabolic plasticity, we explored the novel role of BACE2 in regulating lipid homeostasis and metabolic adaptation. By combining proteomics, metabolomics, and LiP-MS within an integrative R-based analytical framework, we characterized metabolic alterations dependent on BACE2 activity. Our results reveal that BACE2 functions as a regulator of lipid uptake by modulating the shedding of key lipid transporters, thereby preventing excessive lipid influx. Its inhibition enhances lipid uptake, disrupts lipid storage, promotes glutamine-driven lipogenesis, and triggers oxidative stress, ultimately compromising mitochondrial bioenergetics. These perturbations progressively force cells to rely on glucose metabolism, unveiling a potential therapeutic vulnerability. Moreover, succinate dehydrogenase activity appears impaired, further exacerbating mitochondrial dysfunction. Collectively, this work uncovers a previously unrecognized role of BACE2 in sustaining metabolic flexibility in metastatic melanoma, positioning it as both a potential biomarker and a candidate therapeutic target in these aggressive tumors.