Abstract
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.
Highlights
Melanoma is the most aggressive form of skin cancer
No signal was observed from the off-resonance image of MITFlow/AXLhigh melanoma cells, which suggests that these droplets are rich in C-H bonds and are likely lipid droplet (LD) (Figure 1(a))
The mass spectrometry data identified cholesteryl oleate (CE 18 : 1) to be the dominant species. These results indicate that LDs accumulated in MITFlow/AXLhigh melanoma contain an elevated level of unsaturated fatty acids in the form of triglyceride and cholesteryl ester (CE)
Summary
Melanoma is the most aggressive form of skin cancer. When melanoma is caught in its early stages and surgically removed, the prognosis is favorable; once melanoma has metastasized, it becomes difficult to treat [1, 2]. One promising target is melanin, the major pigment in melanoma. A recent study used pump-probe microscopy as an elegant label-free approach to distinguish the two types of melanin in melanoma tissues [8], heralding potential prognostic significance [9]. Despite this advance, loss of microphthalmia-associated transcription factor (MITF), the gene regulating pigmentation, is reported in melanomas with an invasive phenotype [10, 11], indicating an unmet need to identify new molecular markers for detecting aggressive and invasive melanoma
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
