Could lipidomic profiling guide personalized treatments for colorectal cancer?
Lipidomic profiling of colorectal cancer cells (CRC) reveals lipid changes associated with FOLFOXIRI therapeutic resistance, highlighting new potential prognostic biomarkers and personalized therapies.
Employing lipidomic profiling, researchers from the University of Geneva (Switzerland) have identified unique lipid alterations associated with chemotherapy resistance in CRC. Published in International Journal of Molecular Sciences, their findings could help to advance our understanding of treatment resistance, as well as guide new opportunities for personalized treatment strategies.
CRC affects nearly two million people annually, with cases projected to exceed three million by 2040. For men and women combined, it is the second leading cause of cancer death in the world. CRC typically produces little or no symptoms during early stages, meaning late diagnosis at advanced stages contributes to its poor prognosis.
Standard treatments for advanced-stage CRC include FOLFOXIRI, a combination therapy consisting of folinic acid, 5-fluorouracil, oxaliplatin and irinotecan. However, the development of resistance to FOLFOXIRI is common and remains a major challenge in oncology research.
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In previous studies attempting to develop drug combinations that could combat this resistance, the University of Geneva team observed an interesting phenomenon: prolonged drug treatment can significantly alter the lipid composition of cancer cells. The current study sought to investigate this further.
They began by analyzing and comparing the lipid profiles of four patient-derived CRC cell lines before and after treatment with FOLFOXIRI. While some cells were left untreated as controls, other cells were exposed to FOLFOXIRI for up to 60 weeks – the typical duration for treatment resistance to develop.
“Untargeted lipid profiling was performed using liquid chromatography coupled with high-resolution mass spectrometry to distinguish between lipid subspecies,” explained Isabel Meister, Research and Teaching Fellow at the University of Geneva’s School of Pharmaceutical Sciences.
To identify common and specific lipid variations in FOLFOXIRI-sensitive (untreated) and resistant (treated) cells, the team applied a specialized algorithm that combines experimental design and factor analysis to handle highly dimensional data – Analysis of Variance Multiblock Orthogonal Partial Least Squares (AMOPLS).
The researchers identified distinct lipidomic changes linked to chemotherapy resistance, suggesting that these altered lipid species could serve as potential prognostic markers for CRC patients undergoing treatment. In one of the cell lines, resistance to FOLFOXIRI was notably associated with shifts in triglycerides, phosphatidylcholine and cholesteryl ester species. In contrast, the other three cell lines exhibited an increased abundance of phospholipids, mainly hexosylceramide and sphingomyelin.
“These differences can be explained by the different genetic profiles of each individual. Every patient is different. This explains the variability in the effectiveness of treatments, and therefore the importance of a personalized approach,” explained George M Ramzy, Research and Teaching Fellow at the University of Geneva’s School of Pharmaceutical Sciences.
“The identification of altered lipid species could serve as potential prognostic markers of chemotherapy resistance. Additionally, understanding these changes may help to develop new treatment strategies to overcome this resistance, and may play a crucial role in restoring drug sensitivity,” expanded Ramzy.
Although these results are incredibly exciting for future tailored treatment strategies, before clinical application, the next step will involve testing these lipid signatures in freshly isolated tumor samples to ensure their relevance in real-world patient settings.
