Acute Pancreatitis Accelerates Initiation and Progression to Pancreatic Cancer in Mice Expressing Oncogenic Kras in the Nestin Cell Lineage Catherine Carrie` re1,4*, Alison L. Young1, Jason R. Gunn 1 , Daniel S. Longnecker2, Murray Korc1,3,4 1 Department of Medicine, Dartmouth Medical School, Hanover, New Hampshire, United States of America, 2 Department of Pathology, Dartmouth Medical School, Hanover, New Hampshire, United States of America, 3 Department of Pharmacology and Toxicology, Dartmouth Medical School, Hanover, New Hampshire, United States of America, 4 Norris Cotton Cancer Center, Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire, United States of America Abstract Targeting of oncogenic Kras to the pancreatic Nestin-expressing embryonic progenitor cells and subsequently to the adult acinar compartment and Nestin-expressing cells is sufficient for the development of low grade pancreatic intraepithelial neoplasia (PanIN) between 2 and 4 months. The mice die around 6 month-old of unrelated causes, and it is therefore not possible to assess whether the lesions will progress to carcinoma. We now report that two brief episodes of caerulein- induced acute pancreatitis in 2 month-old mice causes rapid PanIN progression and pancreatic ductal adenocarcinoma (PDAC) development by 4 months of age. These events occur with similar frequency as observed in animals where the oncogene is targeted during embryogenesis to all pancreatic cell types. Thus, these data show that oncogenic Kras-driven PanIN originating in a non-ductal compartment can rapidly progress to PDAC when subjected to a brief inflammatory insult. Citation: Carrie`re C, Young AL, Gunn JR, Longnecker DS, Korc M (2011) Acute Pancreatitis Accelerates Initiation and Progression to Pancreatic Cancer in Mice Expressing Oncogenic Kras in the Nestin Cell Lineage. PLoS ONE 6(11): e27725. doi:10.1371/journal.pone.0027725 Editor: Wafik S. El-Deiry, Penn State Hershey Cancer Institute, United States of America Received June 7, 2011; Accepted October 23, 2011; Published November 28, 2011 Copyright: 2011 Carrie`re et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: This work was supported by grants from: The National Cancer Institute: CA- R37-075059 to Murray Korc and CA-127095 to Catherine Carrie`re; The Lustgarten Foundation for Pancreatic Cancer Research to Catherine Carrie`re. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. * E-mail: Carriere@Dartmouth.edu Introduction Pancreatic ductal adenocarcinoma (PDAC) accounts for over 95% of all exocrine pancreatic malignancies and is the fourth leading cause of cancer-related death in the United States, with a median survival of 6 months [1]. In the last 30 years, patient survival rates have not improved substantially, and PDAC remains intractable in its late stages. Thus, there is an urgent need to develop new approaches for early detection of PDAC as well as new therapies targeting early cancer stages. Mouse models of PDAC that recapitulate human cancer have the potential to advance our understanding of the early events in cancer development. PDAC is now recognized to arise predominantly through progression of pancreatic intraepithelial neoplasia (PanIN), ranging from low- (PanIN-1A, -1B) to high-grades (PanIN-2, -3), PanIN-3 representing carcinoma in situ and the immediate precursor to ductal adenocarcinoma [2]. This histologic progres- sion is correlated with the accumulation of genetic abnormalities of which mutations leading to the constitutive activation of KRAS are the earliest and most common (95%) [3]. The first relevant mouse models of PDAC were generated by targeting a conditionally mutated Kras allele (KrasG12D) to early pancreatic progenitors (using Pdx1 and Ptf1a promoters) and subsequently to all pancreatic cell types [4,5]. These models recapitulated faithfully the full spectrum of human PanIN progression and pancreatic cancer development, demonstrating that oncogenic Kras expres- sion is sufficient for PDAC initiation. To delineate the cells of origin of PDAC, several models were subsequently developed where mutated Kras was targeted to more restricted embryonic or adult cell populations. We used a Nestin-Cre driver to target KrasG12D to acinar and Nestin-expressing cells (Nestin-Cre; LSL- KrasG12D or N/K mice) (Fig. 1A), whereas others targeted oncogenic Kras to the acinar only or acinar/centroacinar cells with different elastase-Cre and mist1-Cre drivers [6,7,8,9]. In all these models, PDAC initiation and progression could be observed, demonstrating that PDAC can have a non-ductal origin in mice. Although a recent study suggested that PDAC could initiate in the endocrine compartment, it has been shown that the promoter used in this study could also target a small fraction of acinar cells [10,11]. In all the models where oncogenic Kras was activated during embryogenesis, low-grade PanINs developed, generally progressing over 8–12 months to high-grade lesions and PDAC. We were not able to observe progression to PDAC in N/K mice, as they generally die around age 6 months from of central nervous system complications. Activation of KrasG12D in the adult pancreas led to non- progressing low-grade lesion formation [7,8,12]. However, following induction of chronic pancreatitis, these animals devel- oped high-grade lesions and progressed to PDAC [7]. These data are consistent with epidemiologic studies showing that patients suffering from chronic pancreatitis have a 16-fold increased risk of developing pancreatic cancer [13]. While brief episodes of acute pancreatitis (AP) lead to rapid PanIN progression and increased frequency of PDAC in Pdx1-Cre; LSL-KrasG12D mice [14,15,16], it is unknown if it would also lead to PDAC in the Nestin-driven mouse model. We now show that N/K mice, when subjected to PLoS ONE | www.plosone.org 1 November 2011 | Volume 6 | Issue 11 | e27725