Distinct molecular adaptations underlie convergent phenotypic responses to mannose in normal and metastatic melanocytes.

Mannose has emerged as a promising metabolic modulator capable of impairing tumor growth in phosphomannose isomerase (PMI)-deficient cancers. However, the molecular adaptations underlying the response of melanoma cells to mannose remain poorly understood. Here, we compared the phenotypic, proteomic, and phosphoproteomic responses of normal melanocytes (Melan-A) and metastatic melanoma cells (B16F10) cultured in glucose- or mannose-containing media. Both cell types exhibited similar phenotypic responses to mannose, including reduced growth, altered lactate production, and increased accumulation of acidic vesicles. Despite these shared phenotypes, proteomic and phosphoproteomic analyses revealed markedly distinct molecular adaptations. Mannose induced modest proteomic changes in normal melanocytes but extensive remodeling in metastatic melanoma cells, accompanied by profound phosphoregulatory remodeling. Substrate enrichment analysis based on curated signaling interactions identified phosphosubstrate signatures associated with predominantly homeostatic regulatory programs in normal melanocytes, whereas metastatic cells exhibited phosphosubstrate signatures associated with stress-responsive, survival, cell-cycle, and ubiquitin-mediated regulatory programs. Collectively, our findings demonstrate that similar phenotypic responses to mannose arise from fundamentally distinct molecular programs, highlighting cellular context as a key determinant of the adaptive response to mannose-induced metabolic stress in melanoma.