High-throughput single-cell metabolites profiling reveals metabolic reprogramming confers cisplatin resistance in lung cancer.

Lung cancer is the most common cause of cancer-related deaths worldwide. Platinum-containing two-drug regimens are the standard first-line chemotherapeutic regimen, but acquired resistance remains a major challenge. Cancer cells can evolve and adapt to therapeutic stress by reprogramming their metabolism and passing on drug resistance to neighboring drug-sensitive cancer cells through cell-to-cell interactions. Here, we have developed a method to study the interactions between cells. Using human lung cancer A549 cells, we constructed a drug-sensitive cell line expressing red fluorescent protein and a cisplatin-resistant cell line. Employing label-free mass cytometry, we acquired metabolites information at the single-cell level. Through pseudotime analysis, we identified two most important clusters of metabolites. We discovered that phosphatidylcholines are strongly associated with drug resistance. Through unsupervised learning, we observed that drug-sensitive cells in co-culture transform into a novel cell state after cisplatin treatment. This method offers a novel tool for investigating the mechanisms underlying the development of cancer cell drug resistance.