Background: Dietary
tyrosine regulating
melanoma progression has been well-recognized. However, whether
tyrosine-based
melanin anabolism contributes to pulmonary and cerebral organotropic colonization of
melanoma remains elusive. Furthermore, approaches based on targeting
tyrosinase activity to inhibiting multi-organ
metastasis of
melanoma cells need to be designed and validated. Methods: Patients derived
melanoma cells and mouse
B16 melanoma cells with different pigmentation were employed in this investigation.
Tyrosine content dynamics in
tumors and multiple organs during the
melanoma progression was monitored, and
tyrosine-based
melanin synthesis of
melanoma cells derived from multi-organ was determined. Additionally, we also adopted
RNA-seq, flow cytometry, real-time PCR and composite
metastasis mouse model to analyze organotropic colonization and to validate designed therapeutic strategies. Results:
B16 melanoma cells with high activity of
tyrosinase and sensitivity of
tyrosine utilization for
melanin synthesis (Tyr-H cells) easily colonized in the lung, while
B16 melanoma cells lacking above characteristics (Tyr-L cells) exhibited potent proliferation in the brain. Mechanistically, Tyr-H cells recruited and trained neutrophils and macrophages to establish pulmonary metastatic niche dependent on highly secreted CXCL1 and CXCL2 and an excessive melanosome accumulation-induced cell death. Tyr-L cells enhanced PD-L1 expression in
tumor-infiltrated macrophages when they are progressing in the brain. Accordingly, intervention of
tyrosinase activity (2-Ethoxybenzamide or
hydroquinone) in combination with inhibitors of phagocytosis (
GSK343) or chemotaxis (
SB225002) suppressed organotropic colonization and significantly improved the survival of
melanoma- bearing mice treated with
immune checkpoint blockade (PD1 antibody). Conclusions: The heterogeneity of
melanoma cells in utilization of
tyrosine is associated with organotropic colonization, providing the basis for developing new strategies to combat
melanoma.