Raman-guided subcellular pharmaco-metabolomics for metastatic melanoma cells

• Published in: Nature communications 2020-09, Vol.11 (1), p.4830-4830, Article 4830
• Main Authors: Du, Jiajun, Su, Yapeng, Qian, Chenxi, Yuan, Dan, Miao, Kun, Lee, Dongkwan, Ng, Alphonsus H. C., Wijker, Reto S., Ribas, Antoni, Levine, Raphael D., Heath, James R., Wei, Lu
• Format: Article
• Language: English
• Subjects: 14; 14/63; 140/133; 38/39; 631/1647/527/1821; 631/45/287; 631/67/2327; 631/80/2373; 631/92/555; Apoptosis; Cell Line, Tumor; Fatty Acids - metabolism; Humanities and Social Sciences; Humans; Lipid Droplets; Lipid Metabolism; Lipidomics; Lipids; Melanoma - metabolism; Metabolomics - methods; Microscopy - methods; multidisciplinary; Oleic Acid; Science; Science (multidisciplinary); Spectrum Analysis, Raman - methods; Stearoyl-CoA Desaturase - metabolism; Transcriptome
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-020-18376-x

Non-invasively probing metabolites within single live cells is highly desired but challenging. Here we utilize Raman spectro-microscopy for spatial mapping of metabolites within single cells, with the specific goal of identifying druggable metabolic susceptibilities from a series of patient-derived melanoma cell lines. Each cell line represents a different characteristic level of cancer cell de-differentiation. First, with Raman spectroscopy, followed by stimulated Raman scattering (SRS) microscopy and transcriptomics analysis, we identify the fatty acid synthesis pathway as a druggable susceptibility for differentiated melanocytic cells. We then utilize hyperspectral-SRS imaging of intracellular lipid droplets to identify a previously unknown susceptibility of lipid mono-unsaturation within de-differentiated mesenchymal cells with innate resistance to BRAF inhibition. Drugging this target leads to cellular apoptosis accompanied by the formation of phase-separated intracellular membrane domains. The integration of subcellular Raman spectro-microscopy with lipidomics and transcriptomics suggests possible lipid regulatory mechanisms underlying this pharmacological treatment. Our method should provide a general approach in spatially-resolved single cell metabolomics studies. Single-cell metabolomics can offer deep insights into the metabolic reprogramming that accompanies disease states. Here, the authors use Raman spectro-microscopy for non-invasive metabolite analysis and identification of druggable metabolic susceptibilities in single live melanoma cells.