Using the secondary structure (beta-sheet) of exosomal proteins for noninvasive pancreatic cancer detection

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PROJECT SUMMARY/ABSTRACT With a 5-year survival rate of less than 5%, pancreatic ductal adenocarcinoma (PDAC) as a devastating disease has an inferior prognosis, and prolonged survival is achieved only by resection with macroscopic tumor clearance. Although surgical resection can potentially cure early-stage disease, more than 80% of patients present with locally advanced or metastatic disease at the time of diagnosis and are ineligible for resection. Hence, early detection could significantly reduce mortality and improve prognosis. Exosomes secreted by tumor cells actively participate in tumor progression and metastasis and contain multiple biomolecules reflecting the status of their parental tumor cells. Although the biogenesis is still not clear, exosomes released into circulation are under intensive study mostly for its pivotal clinical potential for non- invasive early detection. Most of these studies focused on exosomal single protein/RNA/DNA, or molecular signatures based on multiplex assays. To date, none of the candidate markers have been validated to be adequate for clinical prognosis or diagnosis, which underlies the problem in current exosomal marker discovery approaches. We studied the collective attribute of exosomes by scrutinizing the secondary structure of the exosomal proteins. Our preliminary data strongly suggest that the tumor cell secretes more β-sheet rich proteins through exosomes than the normal cell. The objective of this proposal is to validate the findings in multiple ways, providing evidence that the secondary structure of the exosomal proteins can be used for cancer detection. Successful data collection and analysis from this low-risk and high-reward study will not only justify that a tumor cell sheds more β-sheet rich proteins through exosomes than a normal cell, but will also uncover an insight into the association between exosomes and pancreatic cancer cell states, thus providing a method that can potentially serve as biomarkers and therapeutic choices for pancreatic cancer.