Objective and Impact Statement.Molecular signatures are needed for early diagnosis and improved treatment of metastatic melanoma.By high-resolution multimodal chemical imaging of human melanoma samples,we identify a m...Objective and Impact Statement.Molecular signatures are needed for early diagnosis and improved treatment of metastatic melanoma.By high-resolution multimodal chemical imaging of human melanoma samples,we identify a metabolic reprogramming from pigmentation to lipid droplet(LD)accumulation in metastatic melanoma.Introduction.Metabolic plasticity promotes cancer survival and metastasis,which promises to serve as a prognostic marker and/or therapeutic target.However,identifying metabolic alterations has been challenged by difficulties in mapping localized metabolites with high spatial resolution.Methods.We developed a multimodal stimulated Raman scattering and pump-probe imaging platform.By time-domain measurement and phasor analysis,our platform allows simultaneous mapping of lipids and pigments at a subcellular level.Furthermore,we identify the sources of these metabolic signatures by tracking deuterium metabolites at a subcellular level.By validation with mass spectrometry,a specific fatty acid desaturase pathway was identified.Results.We identified metabolic reprogramming from a pigment-containing phenotype in low-grade melanoma to an LD-rich phenotype in metastatic melanoma.The LDs contain high levels of cholesteryl ester and unsaturated fatty acids.Elevated fatty acid uptake,but not de novo lipogenesis,contributes to the LD-rich phenotype.Monounsaturated sapienate,mediated by FADS2,is identified as an essential fatty acid that promotes cancer migration.Blocking such metabolic signatures effectively suppresses the migration capacity both in vitro and in vivo.Conclusion.By multimodal spectroscopic imaging and lipidomic analysis,the current study reveals lipid accumulation,mediated by fatty acid uptake,as a metabolic signature that can be harnessed for early diagnosis and improved treatment of metastatic melanoma.展开更多
基金the IUSCC Cancer Center at Indiana University School of Medicine funded by the IU Simon Cancer Center Support Grant P30 CA082709,for the use of the Tissue Procurement and Distribution Core,which provided Frozen Tissue Sample servicesupported by NIH grants R33 CA223581 and R35 GM136223 to JXC。
文摘Objective and Impact Statement.Molecular signatures are needed for early diagnosis and improved treatment of metastatic melanoma.By high-resolution multimodal chemical imaging of human melanoma samples,we identify a metabolic reprogramming from pigmentation to lipid droplet(LD)accumulation in metastatic melanoma.Introduction.Metabolic plasticity promotes cancer survival and metastasis,which promises to serve as a prognostic marker and/or therapeutic target.However,identifying metabolic alterations has been challenged by difficulties in mapping localized metabolites with high spatial resolution.Methods.We developed a multimodal stimulated Raman scattering and pump-probe imaging platform.By time-domain measurement and phasor analysis,our platform allows simultaneous mapping of lipids and pigments at a subcellular level.Furthermore,we identify the sources of these metabolic signatures by tracking deuterium metabolites at a subcellular level.By validation with mass spectrometry,a specific fatty acid desaturase pathway was identified.Results.We identified metabolic reprogramming from a pigment-containing phenotype in low-grade melanoma to an LD-rich phenotype in metastatic melanoma.The LDs contain high levels of cholesteryl ester and unsaturated fatty acids.Elevated fatty acid uptake,but not de novo lipogenesis,contributes to the LD-rich phenotype.Monounsaturated sapienate,mediated by FADS2,is identified as an essential fatty acid that promotes cancer migration.Blocking such metabolic signatures effectively suppresses the migration capacity both in vitro and in vivo.Conclusion.By multimodal spectroscopic imaging and lipidomic analysis,the current study reveals lipid accumulation,mediated by fatty acid uptake,as a metabolic signature that can be harnessed for early diagnosis and improved treatment of metastatic melanoma.
