Don't sugarcoat it: understanding and targeting glycosylation changes in pancreatic and liver cancers

Pancreatic ductal adenocarcinoma (PDAC) and hepatocellular carcinoma (HCC) are leading causes of cancer-related deaths. Despite knowing these cancers’ driver mutations, there are no effective therapies. A universal yet understudied feature of both PDAC and HCC is their aberrant glycosylation.

Glycosylated serum proteins act as clinical biomarkers, but it is unknown how altered glycosylation – driven by gene expression changes and mutations of glycosyltransferases/glycosidases – contributes to disease progression.

First, I propose to establish a new HCC mouse model combining genetic alterations with chronic alcohol consumption, a major risk factor.

Second, I will systematically uncover the glycosylation changes in primary cells of this new HCC model and established PDAC models using unbiased mass spectrometry-based glycomics and lectin microarrays. By applying glycobiological techniques to this setting, I will bring together two hitherto disparate research fields.

Third, based on these data, I will manipulate the glycosyltransferases/glycosidases most likely responsible for the glycosylation changes and examine disease progression, yielding new targetable oncogenes.

In parallel, based on preliminary data, I will investigate the tumour suppressive mechanism of the fucosidase FUCA1 in mouse models of PDAC and HCC, using glycomics as a starting point. Finally, I will validate my findings in human PDAC and HCC samples.