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Nutrient-Delivery and Metabolism Reactivation Therapy for Melanoma

ABSTRACT: To fulfil the demands of rapid proliferation, tumour cells, including those in melanoma, undergo significant metabolic alterations, with some pathways being upregulated while others are downregulated. Suppression of hyperactivated metabolism has been proven to counteract tumour growth. However, whether the reactivation of inversely downregulated metabolic pathways has therapeutic effects remains unexplored. Here, we report a nutrient-based metabolic reactivation strategy for effective melanoma treatment. Briefly, L-tyrosine nanomicelles (MTyr-OANPs) were constructed for targeted supplementation of tyrosine to reactivate melanogenesis in melanoma cells. We found that reactivation of melanogenesis using MTyr-OANPs significantly impedes the proliferation of melanoma cells, primaryly through the inhibition of glycolysis. We discovered that reduced glycolysis was a consequence of pyruvate kinase activity inhibition by melanin intermediates indole-5,6-quinone. Furthermore, leaveraging melanin as a natural photothermal reagent for photothermal therapy (PTT), we demonstrated the complete eradication of tumours in B16F10 melanoma-bearing mice through treatment with MTyr-OANPs and PTT. To the best of our knowledge, this is the first study of metabolism activation-based tumour treatment, suggesting specific nutrients as potent activators of metabolic pathways.

ORGANISM(S): Mus musculus

PROVIDER: GSE263479 | GEO | 2024/04/11

REPOSITORIES: GEO

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Project description: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, how to inhibit multi-organ metastasis by interfering tyrosinase activity of melanoma cells and function of immunocytes needs to be designed and validated. Patients derived melanoma cells and mouse B16 melanoma cells with different pigment were employed in this investigation. Tyrosine content dynamics in tumors and multiple organs during the melanoma progression were monitored, and tyrosine-based melanin synthesis ability of melanoma cells derived from multi-organ were detected. Additionally, we also adopted the RNA-seq, flowcytometry, real-time PCR and composite metastasis mouse model to analyze organotropic colonization and to design therapeutic strategies. 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 without above characteristics (Tyr-L cells) exhibited potent proliferation in the brain. Mechanistically, Tyr-H cells recruited and trained neutrophils and macrophages to build up the pulmonary metastatic niche dependent on highly secreted CXCL1 and CXCL2 and an excess 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), together with inhibitors to phagocytosis (GSK343) or chemotaxis (SB225002) suppress organotropic colonization and significantly improve the survival of immune checkpoint blockade (PD1 antibody) treated melanoma bearing mice. The heterogeneity of melanoma cells in utilization of tyrosine is associated with organotropic colonization, providing the basis for developing strategies to combat melanoma and prevent their metastasis.

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Nutrient-Delivery and Metabolism Reactivation Therapy for Melanoma

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