The biological role of Sphingolipids in pancreatic cancer
Employing metabolomics, the ‘omics technique’ that can furnish a dynamic portrait of metabolic profiles, we delineated a metabolic signature discriminating between chronic pancreatitis and pancreatic cancer, which in an unsupervised analysis suggested sphingolipids independent of tumour burden to be the best discriminating group of metabolites. In addition, our recent finding in a cohort of resected PDAC patients (ESPAC-3 trial) revealed a strong correlation of acid sphingomyelinase (aSMase; a key enzyme in sphingolipid biogenesis) with resistance to gemcitabine treatment, further supporting a role of sphingolipid metabolism in PDAC biology. In this project, we will extend our studies on the role of sphingolipid metabolism. We will perform analyses at multiple levels, including target discovery and functional annotation.
First, we will perform unbiased global metabolic profiling of cell lines and organoids from genetically engineered PDAC mouse models and will cross-correlate findings to parallel metabolomic profiling in human organoids and patients enrolled in a prospective clinical study. This comprehensive discovery effort will define dynamics of metabolic changes during disease initiation and progression and will link metabolic landscapes with disease and drug resistance phenotypes.
Second, we will perform in vivo functional studies using aSMAse-deficient mice to uncover cell-autonomous and non-autonomouse aSMAse functions.
Finally, the role of aSMAse in response and resistance to various clinically relevant drugs will be assessed using mouse and human cell-based models. Knowledge gained in these studies will be used to target aSMAse in different cellular compartments in mice. Using aptamers we have generated a system which will allow us targeted transport of biologically active compounds (inhibitors) to pancreatic cancer cells in endogenous cancer models. We will develop the system further to also allow targeted delivery to cells of the microenvironment in the future.
Our studies will give comprehensive insights into the role of sphingolipid metabolism in PDAC biology and will explore novel potential avenues for therapeutic intervention.
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