The treatment of pancreatic adenocarcinoma remains a clinical challenge. The majority of patients are diagnosed at an advanced stage beyond what current therapy can benefit. Most patients have a vague prodrome of symptoms prior to diagnosis making early detection difficult and therefore uncommon 
. Currently no clinically useful interventions to screen for patients with PDAC are available. The purpose of this project was to evaluate the protein expression profiles of pancreatic juice samples harvested from the pancreatic duct at the time of surgery to potentially identify unique markers that could be used to differentiate benign from malignant pancreatic masses and further delineate different grades of PDAC. 65 proteins were specifically seen only in adenocarcinomas and 4 proteins were observed solely in the benign pancreatic masses. Further, a total of 56 proteins were elevated in pancreatic juice of PDAC compared to benign controls. Of interest, these differentiating profiles revealed the unique presence of proteins associated with Parkinson's disease namely: aSyn and PARK7 
. The presence of aSyn in PDAC has not been reported in the literature and previous mouse/drosophila models for this protein have not reported alterations in pancreas function or incidence of pancreatic cancer 
. However, elevated expression of aSyn has been recently reported in melanoma 
, while its isoform gamma-synuclein (γSyn) a.k.a. Breast Cancer Specific Protein-1 has been shown to be elevated in tumors of breast, uterine, colorectal and pancreas 
. Further, γSyn that has 63% identity to aSyn at the protein level, has been reported to potentiate invasion in these tumors 
. In light of this, it was interesting to observe higher levels of aSyn in PDAC. Specifically our tissue arrays demonstrate strong staining for aSyn in tumors compared to moderate to weak staining for benign masses. Of further interest, this protein expressed in a subset of PDAC patients was identified in its aggregated form. This aggregation is characteristic of Lewy Bodies seen in Parkinson's disease which is thought to contribute to the degenerative disease process 
. Similarly, elevated levels of an additional Parkinson's disease associated protein PARK7 (DJ1) 
, in pancreatic ductal juice of adenocarcinomas corroborate an earlier report 
. Also other studies have documented DJ-1 over-expression to be associated with moderately differentiated PDAC 
. Furthermore, DJ-1 has been reported to protect neuronal cells from apoptosis 
while function as an oncogene in tumor cells 
. However, the exact mechanism by which PARK-7 exerts its oncogenic effect is not clearly understood, although it is presumed to involve p38 mitogen activated-protein kinase signaling 
. These results are indicative of a link between PDAC and neurodegenerative disease like Parkinson's disease that will need to be further investigated.
In addition to the above findings, the PDAC-associated secretory proteome also revealed elevated levels of a number of additional metabolic enzymes. One of these was Purine Nucleoside Phosphorylase (NP), the rate limiting enzyme in salvage pathway involving purines, which is operational during inflammation as well as neoplastic progression, and has been highly targeted by various chemotherapeutic agents 
. In cancers, NP activity has been previously reported to be high in cancer sera 
. NP expression has also been used to determine the clinical severity of various types of leukemias and lymphomas especially as a ratio to adenosine deaminase (ADA)
. Likewise in the area of inflammation, NP deficiency has been reported in immune deficient syndromes, like severe combined immunodeficiency syndrome (SCID) 
. This strong association of NP with inflammation and its earlier use in assessing severity of leukemia/lymphoma motivated us to evaluate the expression and activity of this protein in PDAC, specifically in patients with antecedent inflammatory conditions like chronic pancreatitis. Furthermore, previous investigations have correlated chronic pancreatitis and the development of pancreatic intraepithelial neoplasia (PanIN) 
. Thus there are strong correlates to suggest that antecedent chronic inflammation could be a known factor to develop PanIN or PDAC and NP may be a useful marker to monitor the progression from inflammation to PDAC.
Importantly, no previous studies have considered measuring expression of NP protein or its regulated metabolites in PDAC. Our results on NP protein levels in sera show the presence of two bands at ~32 KDa predominantly in PDAC sera compared to controls. Among these, we presume the differential upper band seen in PDAC sera could represent the phosphorylated form of the protein. Although this needs to be validated in PDAC, NP phosphorylation has been earlier reported in neuronal cells exposed to oxidative stress 
. Further, in a proof-of-concept setting, our results also show alterations in levels of metabolic intermediates downstream of NP, in PDAC sera, alluding to the existence of an active NP-driven purine salvage pathway in these tumors. This could be an adaptive mechanism developed by PDAC to elude the toxicity of chemotherapeutics as well as the cytotoxic effects of the chronic and intense inflammatory cascade often associated with the tumor; a hypothesis that needs further investigation. Importantly, from a biomarker development perspective, these findings will need to be validated in larger cohort of independent clinical specimens. Furthermore, it will be interesting to focus future investigations on evaluating the potential of NP to predict PDAC's with antecedent chronic pancreatitis and the influence on the development of PanINs in the inflammatory milieu.
In summary, the study describes the secretory proteomic profiles for PDAC which reveals a Parkinson's signature suggestive of a possible nuance between pancreatic tumors and the neurodegenerative disorder. Furthermore, the secretory profiles reveal NP to be elevated in PDAC, indicative of a reliance of the tumor on the salvage pathway. Importantly, levels of NP-regulated metabolites in serum were able to distinguish PDAC from benign patients highlighting its potential for future biomarker development. This finding sets the stage to evaluate NP as a possible marker to predict PDAC with antecedent pancreatitis, a clinical challenge that currently has no predictive markers.