Abstract B06: Maintenance of acinar cell differentiation prevents KRAS-driven pancreatic cancer initiation
Authors: Krah Nathan M. , Yugawa Deanne E. , Straley Julie A. , Narayanan Shuba M. , Azevedo-Pouly Ana C. , Murtaugh L. Charles 
Published: December 2017

Abstract
The primary goal of this study is to determine whether sustained expression of the acinar differentiation determinant, PTF1A, is sufficient to prevent and/or reverse KRAS-driven pancreatic cancer initiation. With a 5-year survival of only ~6%, pancreatic ductal adenocarcinoma (PDAC) remains one of the worst prognoses in medicine. In most clinical cases, PDAC is detected after the primary tumor has metastasized, leaving limited treatment options. Our lab is interested in understanding the initiating events that drive early tumorigenesis, which may provide new targets for early intervention. Activating mutations in the “un-druggable” proto-oncogene KRAS are found in over 90% of human PDAC cases, and expression of an oncogenic Kras mutant (KrasG12D) in the acinar epithelium of adult mice recapitulates formation of precancerous pancreatic intraepithelial neoplasia (PanIN) [1]. Because formation of PanINs takes months in these mouse models despite nearly ubiquitous KrasG12D expression, we hypothesized that acinar cell differentiation programs might suppress the transforming ability of this oncogene. Indeed, recent conditional-knockout studies from our lab demonstrate that downregulation of Ptf1a, the master transcriptional regulator of acinar cell differentiation, is rate-limiting for KRAS-driven PanIN formation and subsequent PDAC formation [2]. These findings suggest that acinar cell differentiation may serve as a barrier to tumor development by blocking the earliest phases of oncogenesis. We therefore hypothesized that sustaining Ptf1a expression during pancreatic cancer initiation/progression would inhibit or reverse disease. To test this hypothesis, we generated a Cre- and doxycycline-dependent Ptf1a gain-of function (GOF) mouse model on a KrasG12D background. Eight weeks after we induced recombination, mice expressing both oncogenic KrasG12D and GOF-Ptf1a had a significantly reduced PanIN burden compared to mice expressing KrasG12D alone, suggesting that preservation of acinar cell differentiation does limit pancreatic tumor initiation. Examination of PanINs in KrasG12D + GOF-Ptf1a pancreata revealed that PTF1A expression was completely lost in the few precancerous lesions that did form, suggesting that the cells contributing to these lesions were escapers that did not express transgenic Ptf1a. Taken together, these results suggest that silencing of Ptf1a is a necessary step in PDAC initiation. In ongoing studies, we are using KrasG12D + GOF-Ptf1a mice to test whether reintroduction of Ptf1a into established PanINs can revert these cells to a quiescent phenotype in vivo, and we will present these preliminary data at this meeting. Our results to date suggest that acinar differentiation provides a novel, epigenetic barrier to tumor initiation and highlight the potential importance of cell differentiation in solid tumors [3]. Going forward, we propose that studying cell differentiation in other tumor types may provide insight to disease initiation and potential treatment.
1. De La, O.J., et al., Notch and Kras reprogram pancreatic acinar cells to ductal intraepithelial neoplasia. Proc Natl Acad Sci U S A, 2008. 105(48): p. 18907-12.
2. Krah, N.M., et al., The acinar differentiation determinant PTF1A inhibits initiation of pancreatic ductal adenocarcinoma. Elife, 2015. 4.
3. Krah, N.M. and L.C. Murtaugh, Differentiation and inflammation: best enemies in gastrointestinal carcinogenesis. Under review.
Citation Format: Nathan M. Krah, Deanne E. Yugawa, Julie A. Straley, Shuba M. Narayanan, Ana C. Azevedo-Pouly, L. Charles Murtaugh. Maintenance of acinar cell differentiation prevents KRAS-driven pancreatic cancer initiation [abstract]. In: Proceedings of the AACR International Conference: New Frontiers in Cancer Research; 2017 Jan 18-22; Cape Town, South Africa. Philadelphia (PA): AACR; Cancer Res 2017;77(22 Suppl):Abstract nr B06.