Metabolic Characterization of Plasma and Cyst Fluid from Cystic Precursors to Pancreatic Cancer Patients Reveal Metabolic Signatures of Bacterial Infection

Pancreatic
cancer is the seventh leading cause of cancer-related
death worldwide, with a 5 year survival rate as low as 9%. One factor
complicating the management of pancreatic cancer is the lack of reliable
tools for early diagnosis. While up to 50% of the adult population
has been shown to develop precancerous pancreatic cysts, limited and
insufficient approaches are currently available to determine whether
a cyst is going to progress into pancreatic cancer. Recently, we used
metabolomics approaches to identify candidate markers of disease progression
in patients diagnosed with intraductal papillary mucinous neoplasms
(IPMNs) undergoing pancreatic resection. Here, we enrolled an independent
cohort to verify the candidate markers from our previous study with
orthogonal quantitative methods in plasma and cyst fluid from serous
cystic neoplasm and IPMN (either low- or high-grade dysplasia or pancreatic
ductal adenocarcinoma). We thus validated these markers with absolute
quantitative methods through the auxilium of stable isotope-labeled
internal standards in a new independent cohort. Finally, we identified
novel markers of IPMN status and disease progressionincluding
amino acids, carboxylic acids, conjugated bile acids, free and carnitine-conjugated
fatty acids, purine oxidation products, and trimethylamine-oxide.
We show that the levels of these metabolites of potential bacterial
origin correlated with the degree of bacterial enrichment in the cyst,
as determined by 16S RNA. Overall, our findings are interesting per
se, owing to the validation of previous markers and identification
of novel small molecule signatures of IPMN and disease progression.
In addition, our findings further fuel the provoking debate as to
whether bacterial infections may represent an etiological contributor
to the development and severity of the disease in pancreatic cancer,
in like fashion to other cancers (e.g., Helicobacter
pylori and gastric cancer).