Background: Pancreatic cancer-related diabetes (PCRD) is a paraneoplastic condition driven by metabolic dysfunction preceding the clinical diagnosis of pancreatic cancer. Exosomes, small extracellular vesicles secreted by tumour and stromal cells, are increasingly recognised for their role in mediating intercellular communication and metabolic reprogramming. We have previously shown that mouse exosomes derived from pancreatic cancer and stellate cell co-cultures impair insulin secretion by beta cells and insulin signalling pathway factors in hepatocytes and identified potential protein and RNA mediators in exosome cargo. This study aimed to characterise the lipid cargo in cancer cell (KPC) and pancreatic stellate cell (PSC)-derived exosomes.
Methods: Liquid chromatography triple quadrupole mass spectrometry (LC-QQQ-MS) was utilised to characterise the lipid composition of exosomes and cell pellets derived from mouse PSC-ex, pancreatic cancer cells (KPC-ex), and their co-cultures (PSC+KPC-ex).
Results: A total of 451 lipid species were identified, spanning multiple lipid classes including phospholipids, sphingolipids, triglycerides, and cholesteryl esters. Comparative analysis revealed distinct lipid signatures between exosomes and their parent cells, with PSC+KPC-ex showing selective enrichment in lactosylceramide (LacCer), a glycosphingolipid implicated in insulin resistance, inflammation, and cancer progression. Hierarchical clustering and volcano plot analyses demonstrated that lipid packaging into exosomes was not random but modulated by tumour-stroma interactions. LacCer was consistently enriched in co-culture exosomes compared to KPC counterparts, suggesting its potential utility as a biomarker for early detection of PCRD. PSC-derived exosomes were enriched in lysophosphatidylcholines (LPCs) such as LPC 16:0 and LPC 22:5, which have been shown to stimulate insulin secretion and modulate inflammation. KPC exosomes contained higher levels of GM3(d18:1_24:0), PE(16:0_20:3), and SM(d18:1_16:1), which are associated with insulin signalling disruption and cancer-related membrane remodelling.
Conclusion: This study has identified for the first time, specific lipids in pancreatic cancer and stellate cell-derived exosomes, that may play a role in modulating glucose homeostasis and inflammatory processes associated with pancreatic cancer.