Oncogenic insults within the pancreatic ductal glands produce pre-malignant lesions and PDAC

Abstract public domain (NIH RePORTER)

PROJECT SUMMARY Pancreatic cancer remains a lethal cancer in part because of our lack of understanding of its progression and pathogenesis. Dysregulation of normal progenitor cells can result in the initiation of cancer. An often-overlooked epithelial progenitor niche of the pancreas are the pancreatic ductal glands (PDGs), which are blind outpouches stemming from the main pancreatic duct. Previous analyses have shown an enrichment of pluripotent potential and pancreatic cancer pathways within cells of the PDGs. Cells expressing trefoil factor family 2 (TFF2) give rise to differentiated progeny that migrate to the ductal epithelium during pancreatitis; in-vivo TFF2 knockout experiments have shown these cells are crucial for regeneration of the ductal epithelium. The contribution of this progenitor niche to PDAC initiation and progression remains largely unexplored. Transgenic mice were developed in which expression of Cre-recombinase can be induced within TFF2 expressing cells (Tff2CreERT). Mice with Cre-dependent oncogenes and a dual-color fluorescent reporter (KrasLSL- G12D; P53fl/fl or Smad4fl/fl; Rosa26mT/mG) were crossed with these animals allowing for simultaneous activation of oncogenes and permanent GFP tagging of TFF2 expressing cells of the PDGs and subsequent progeny. Preliminary data show that TFF2-expressing PDG cells exhibit increased stemness following oncogenic activation and give rise to a wide spectrum of lineage traced premalignant lesions and cancers. Our central hypothesis is that the activity of oncogenic insults in PDG cells with stem-like properties results in unique lineage specification and transformation, producing premalignant and malignant lesions similar to those observed in humans.

Public health relevance public domain (NIH RePORTER)

PROJECT NARRATIVE Pancreatic cancer (PDAC) continues to have an extremely poor prognosis, with the 5-year survival rate of those diagnosed less than 5 percent. A broader understanding of PDAC initiation and the earliest events of disease progression is needed for the development of better early detection methods and new therapies. Our preliminary results suggest specific cells of the adult pancreas may contain a cell of origin for PDAC; the proposed research will utilize a genetically engineered mouse model to interrogate the capacity of these cells to initiate precancerous lesions and cancer, helping us to gain new insights into human disease.