Uncovering Plasma Exosomal Lipid Patterns for Early Detection of Pancreatic Cancer

Despite the pioneering work of the Nobel laurate Dr. O. Warburg in the 1920's to 1950's, cancer metabolism was not generally recognized as a "Hallmark" of human cancer until 2011. This is in part due to the lack of understanding of the complexity of human cancer metabolism and the lack of technology to unravel this complexity. I pioneered the development of Stable Isotope Resolved Metabolomics (SIRM) technology in the early 2000's and was the first to apply it to study in detail how metabolic pathways are reprogrammed in human lung cancer patients in vivo, which led to the discovery of enhanced mitochondrial metabolism via the activation of an enzyme pyruvate carboxylase. Prior to my work, mitochondrial metabolism was thought to be dysfunctional. I have since extended the SIRM approach to several preclinical models including ex vivo cultures of human patient tissues, which can predict how cancer patients respond to therapy. Unlike radiotracers, stable isotope tracers are universally safe for use in biological systems. My approach has now been widely adopted by many cancer biologists to uncover many reprogrammed metabolic events in cancer, some of which have been pursued for therapeutic purposes. Our state-of-the-art metabolomics technology also enabled the exploration of novel metabolites as early-detection cancer biomarkers. I first noted the marked difference in lipid composition between tumors and the surrounding benign lung tissues, which led to the hypothesis that the tiny lipidic vesicles, known as &"exosomes" released by cancer tissues into the circulating blood can carry some of the distinct lipids, thereby revealing the cancer status. I tested this hypothesis on the blood plasma exosomes of healthy volunteers versus lung cancer, and found that a set of exosomal lipids can distinguish early-stage lung cancer patients from healthy subjects. I also found that lung and breast cancer patients differed in their plasma exosomal lipids, which can be exploited to inform the occurrence of different cancers. Despite its relatively low incidence, pancreatic cancer is now the #3 deadliest cancer in the US with no good treatment options. A major concern is that the incidence of this cancer is rising, particularly in the Appalachian Kentucky. Early detection coupled with surgery is the best strategy for combating pancreatic cancer as it is highly metastatic and extremely difficult to treat. Our pilot data suggest that plasma exosomal lipids are promising tools for detecting not only early-stage but also precancerous states of pancreatic cancer. I plan to pursue further this exciting research with the Women Strong award so that I can gather more powerful evidence for attracting large extramural funds. To move this finding from the bench to the bed side, I have assembled a strong interdisciplinary team including Drs. J. Kim (Chief of Surgical Oncology), R. Higashi (Co-Director of CESB), S. Mardini (Director of Interventional Endoscopy), T. Barrett (Chief of Gastroenterology), and C. Wang (Director of Markey Cancer Center Bioinformatic core facility). If successful, this research will lead to a tremendous benefit in both pancreatic cancer prevention and patient care.