Abstract
Pancreatic cancer stem cells (PCSCs) play a key role in the aggressiveness of pancreatic ductal adenocarcinomas (PDAC); however, little is known about their signaling and metabolic pathways. Here we show that PCSCs have specific and common proteome and lipidome modulations. PCSCs displayed downregulation of lactate dehydrogenase A chain, and upregulation of trifunctional enzyme subunit alpha. The upregulated proteins of PCSCs are mainly involved in fatty acid (FA) elongation and biosynthesis of unsaturated FAs. Accordingly, lipidomics reveals an increase in long and very long-chain unsaturated FAs, which are products of fatty acid elongase-5 predicted as a key gene. Moreover, lipidomics showed the induction in PCSCs of molecular species of cardiolipin with mixed incorporation of 16:0, 18:1, and 18:2 acyl chains. Our data indicate a crucial role of FA elongation and alteration in cardiolipin acyl chain composition in PCSCs, representing attractive therapeutic targets in PDAC.
Highlights
Pancreatic cancer stem cells (PCSCs) play a key role in the aggressiveness of pancreatic ductal adenocarcinomas (PDAC); little is known about their signaling and metabolic pathways
The results showed a decrease of CYCLIN B1, and an increase of FRIZZLED 2 (FZD2) in all the four PCSCs compared to P cell lines
PCSCs play a crucial role in PDAC initiation and metastasis and are responsible for resistance to chemotherapy and radiation, these cells are still not completely characterized from a molecular point of view
Summary
Pancreatic cancer stem cells (PCSCs) play a key role in the aggressiveness of pancreatic ductal adenocarcinomas (PDAC); little is known about their signaling and metabolic pathways. Abbreviations PDAC Pancreatic ductal adenocarcinoma PCSCs Pancreatic cancer stem cells CSCs Cancer stem cells HADHA Hydroxyacyl-CoA dehydrogenase subunit alpha, trifunctional enzyme CL Cardiolipin FA Fatty acid. PDAC arises in exocrine glands of the pancreas[1,2] and characterises 85% of pancreatic cancer cases It represents the eleventh most common cancer worldwide[3] and the seventh leading cause of cancer-related deaths in the world, being on track to become the second most common cause of cancer-related deaths by 2 0301. In the current study proteomic and lipidomic analyses were integrated to investigate the signaling and metabolic dysfunctions implicated in the pathophysiology of PCSCs obtained from parental (P) PDAC cell lines. The results shown here support the potential of a multiomic approach and contribute to the understanding of PDAC biology revealing mitochondrial cardiolipin remodelling, as well as enhanced fatty acid elongation and phosphoinositol phosphatase pathways, as promising targets in PCSCs
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