Elucidating the Molecular Mechanisms of Pancreatic Ductal Adenocarcinoma Associated New-Onset Diabetes Mellitus: A Path Towards Earlier Detection
Introduction
Pancreatic ductal adenocarcinoma (PDAC) is estimated to become the second leading cause of cancer death in the United States by 2030. Improvement in 5-year survival for PDAC will require advances in early detection to improve resectability rates and the development of improved chemotherapy modalities to prolong survival following resection. Interestingly, approximately 85% of individuals with pancreatic cancer experience diabetes or hyperglycemia. Importantly, approximately 50% of PDAC patients present with diabetes months to a couple of years before the clinical detection of PDAC, with fasting blood glucose levels becoming progressively higher until PDAC diagnosis, a phenomenon known as new-onset diabetes (NOD). Patients who are 50 years or older, undergo weight loss at least one year prior to PDAC diagnosis and develop diabetes prior to clinical detection of PDAC have been identified as a high-risk group for PDAC; with a 7-8 fold higher incidence of PDAC within a 3-year period. Due to onset of diabetes occurring 2-3 years prior to PDAC diagnosis, NOD may represent an opportunity for earlier detection while the tumor is still resectable. Importantly, over half the pancreatic cancer patients undergoing surgery with NOD have their diabetes paradoxically resolved postoperatively, whereas no effect is observed in those with long-standing diabetes, suggesting that impaired glucose tolerance is caused by the tumor itself. Although clinical studies have identified a possible at-risk group for early detection of PDAC, the mechanism for why a subset of patients develop hyperglycemia and why others do not needs to be determined. Additionally, there is currently no validated evidence of the molecular mechanisms leading to the PDAC-NOD phenomenon.
Methods
To determine candidate mediators of pancreatic β-cell dysfunction and insulin resistance in patients with PDAC-NOD, we will utilize orthogonal screening with spatial transcriptomic platforms and functional validation studies utilizing ex vivo and archival human tissues. The biospecimens utilized will be obtained from patients with PDAC presenting with and without NOD, and will include both tumor regions, as well as healthy adjacent tissue. To determine the effect of cancer-derived EVs on β-cell function and peripheral insulin signaling, we will inoculate immortalized or primary human islets and mature adipocytes models with purified exosomes from commercial PDAC or patient-derived cell lines and plasma of patients. Effects on acute and chronic β-cell function and lipolysis will be determined, respectively. We will then purify exosomes from healthy commercial pancreatic duct epithelial cells, patient-derived cell lines, and plasma of patients to determine if circulating EV cargo, including miRNA and proteins, differs between NOD patients who harbor an occult PDAC (cases) versus those with NOD only (controls), and conduct extensive profiling of EVs isolated from serial plasma samples. Affinity-based proteomic profiling and HTG-Edge will be utilized to conduct the initial proteomic and miRNA characterization of PDAC-NOD patient plasma extracellular vesicles between cases and controls, respectively.
Results
We hypothesize that PDAC-associated NOD is a paraneoplastic phenomenon caused by diabetogenic molecules carried and transferred by cancer-derived EVs, primarily to β-cells, leading to perturbation of signaling pathways that cause β-cell dysfunction and insulin resistance. Furthermore, we hypothesize that assessment of cargo found within cancer-derived EVs in patients with NOD, will identify sensitive biomarkers for early detection of PDAC.
Conclusion
The proposed study aims to identify biological factors associated with PDAC-NOD that will form the basis for developing improved preclinical models of PDAC for studying the impact of hyperglycemia on natural history, opportunities to revert the deleterious effects, and identify blood-based biomarkers for early detection in the future.