Abstract 4521: Mutant Kras expression triggers clonal acinar cell expansion as an early step in pancreas cancer

Pancreatic ductal adenocarcinoma (PDA) is the third leading cause of cancer-related deaths in the United States with the lowest 5-year survival rate of any major cancer, in part due to late detection of the disease. Studies indicate that pre-invasive lesions - pancreatic intraepithelial neoplasias (PanINs) - progress to PDA. The cell of origin for PDA is still under debate. While lineage-tracing experiments in mice indicate that PanINs originate from acinar cells, cell culture studies suggest that ductal cells can give rise to PanINs. In addition to these important questions regarding cancer initiation, mechanisms of cellular renewal in the exocrine pancreas remain poorly understood. The enzyme telomerase is intimately associated with cancer, and with stem cells and tissue renewal. Telomerase is required for long-term cell proliferation through its critical role in maintaining telomeres. The core enzyme consists of the RNA component TERC and the reverse transcriptase TERT. Moreover, telomerase is activated in over 90% human cancers and genome wide association studies have linked polymorphisms in the Tertgene with an increased risk of pancreas cancer. To analyze the role of TERT-expressing cells in the pancreas during homeostasis, regeneration and tumorigenesis, we generated a mouse line that expresses the regulated CreERT2 recombinase under the endogenous TERT promoter (TertCreERT2/+). Crossing these mice to a reporter strain enables the permanent labeling of TERT-expressing cells and their progeny upon tamoxifen injection. We find that rare TERT+ cells exist throughout the pancreas within the acinar and islet cell populations, but not in ductal cells. We show that rare TERT+ acinar cells clonally expand to renew the acinar compartment during homeostasis and during pancreas injury. To understand how these TERT+ acinar progenitor cells respond to mutant Kras, we crossed TertCreERT2/+mice with KrasLoxStopLox-G12D/+mice. We find that activation of KrasG12D in TERT-expressing cells in adult mice promotes accelerated acinar clone formation and these acinar lesions ultimately convert to PanIN pre-invasive lesions. Our data indicate that TERT-expressing cells represent an acinar progenitor cell population. Furthermore, these progenitor cells respond to mutant Kras first through a regenerative response yielding expanding acinar clones, followed by conversion to ductal PanIN lesions. We propose that acinar cell expansion is an early step in pancreatic tumorigenesis that precedes ADM and PanIN formation. Citation Format: Steven E. Artandi, Patrick Neuhofer, Caitlin M. Roake, Stewart Kim, Ryan Lu, Greg Charville. Mutant Kras expression triggers clonal acinar cell expansion as an early step in pancreas cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4521.