Role of Pancreatic Cancer-derived Exosomes in Salivary Biomarker Development

Chang Lau,Yong Kim,David Chia,Nadine Spielmann,Guido Eibl,David Elashoff,Fang Wei,Yi-Ling Lin,Aune Moro,Tristan Grogan,Samantha Chiang,Eric Feinstein,Christopher Schafer,James Farrell,David T.W Wong

doi:10.1074/jbc.m113.452458

Abstract

Recent studies have demonstrated that discriminatory salivary biomarkers can be readily detected upon the development of systemic diseases such as pancreatic cancer, breast cancer, lung cancer, and ovarian cancer. However, the utility of salivary biomarkers for the detection of systemic diseases has been undermined due to the absence of the biological and mechanistic rationale as to why distal diseases from the oral cavity would lead to the development of discriminatory biomarkers in saliva. Here, we examine the hypothesis that pancreatic tumor-derived exosomes are mechanistically involved in the development of pancreatic cancer-discriminatory salivary transcriptomic biomarkers. We first developed a pancreatic cancer mouse model that yielded discriminatory salivary biomarkers by implanting the mouse pancreatic cancer cell line Panc02 into the pancreas of the syngeneic host C57BL/6. The role of pancreatic cancer-derived exosomes in the development of discriminatory salivary biomarkers was then tested by engineering a Panc02 cell line that is suppressed for exosome biogenesis, implanting into the C56BL/6 mouse, and examining whether the discriminatory salivary biomarker profile was ablated or disrupted. Suppression of exosome biogenesis results in the ablation of discriminatory salivary biomarker development. This study supports that tumor-derived exosomes provide a mechanism in the development of discriminatory biomarkers in saliva and distal systemic diseases.

Highlights

Salivary biomarkers for systemic diseases have been undermined due to lack of mechanistic and biological rationale
This study demonstrates that a discriminatory panel of transcriptomic salivary biomarkers presents itself upon the development of pancreatic cancer in mice
Even though Apbb1ip was still significantly up-regulated in the saliva of pancreatic cancer mouse saliva, inhibition of exosomes drastically decreased the fold difference between cancer and noncancer saliva. These results suggested that tumor-derived exosomes might be involved in the connectivity between the pancreatic tumors and the oral cavity leading to pancreatic cancer-specific transcriptomic biomarkers in saliva

Summary

Background

Salivary biomarkers for systemic diseases have been undermined due to lack of mechanistic and biological rationale. We recently showed that breast cancer-derived exosome-like microvesicles are capable of activating transcription in salivary gland cells and altering the salivary gland cellderived exosome-like microvesicles both proteomically and transcriptomically (5) These findings suggested that tumorderived exosomes could function as the shuttle between the distal tumor and the oral cavity leading to the development of discriminatory salivary biomarkers. We demonstrated that inhibiting the biogenesis and secretion of exosomes at the tumor source disrupted the panel’s pancreatic cancer-specific transcriptomic salivary biomarkers The findings of this in vivo study illustrated that the inhibition of pancreatic cancer-derived exosomes in mice altered the diseasespecific salivary transcriptomic biomarker profile, supporting that tumor-derived exosomes play a role in the development of disease-specific discriminatory biomarkers in saliva

EXPERIMENTAL PROCEDURES

RESULTS

DISCUSSION