The acinar differentiation determinant PTF1A inhibits initiation of pancreatic ductal adenocarcinoma.

Nathan M Krah,Raymond J Macdonald,Mary P Bronner,Christopher Ve Wright,Jean-Paul De La O,Fong Chen Pan,Spencer G Willet,Chinh Q Hoang,L Charles Murtaugh,Gabriela M Cash,Galvin H Swift

doi:10.7554/elife.07125

Abstract

Understanding the initiation and progression of pancreatic ductal adenocarcinoma (PDAC) may provide therapeutic strategies for this deadly disease. Recently, we and others made the surprising finding that PDAC and its preinvasive precursors, pancreatic intraepithelial neoplasia (PanIN), arise via reprogramming of mature acinar cells. We therefore hypothesized that the master regulator of acinar differentiation, PTF1A, could play a central role in suppressing PDAC initiation. In this study, we demonstrate that PTF1A expression is lost in both mouse and human PanINs, and that this downregulation is functionally imperative in mice for acinar reprogramming by oncogenic KRAS. Loss of Ptf1a alone is sufficient to induce acinar-to-ductal metaplasia, potentiate inflammation, and induce a KRAS-permissive, PDAC-like gene expression profile. As a result, Ptf1a-deficient acinar cells are dramatically sensitized to KRAS transformation, and reduced Ptf1a greatly accelerates development of invasive PDAC. Together, these data indicate that cell differentiation regulators constitute a new tumor suppressive mechanism in the pancreas.

Highlights

Pancreatic ductal adenocarcinoma (PDAC) has a dismal prognosis, with a 5-year survival rate around 5% and a cure rate approaching zero
We have previously demonstrated that Ptf1a expression is lost when activated Notch and KrasG12D work synergistically to reprogram acinar cells into pancreatic intraepithelial neoplasia (PanIN) (De La et al, 2008)
Given that Ptf1a is a central regulator of acinar cell gene expression, we hypothesized that this transcription factor should be downregulated when acinar cells are transformed by oncogenic KrasG12D alone, as well as in human PanINs

Summary

Introduction

Pancreatic ductal adenocarcinoma (PDAC) has a dismal prognosis, with a 5-year survival rate around 5% and a cure rate approaching zero. The most up-to-date chemotherapy regimens extend life only minimally (Ryan et al, 2014), and patients undergoing resection of ostensibly local tumors almost invariably succumb to recurrent disease. While this observation suggests that PDAC is usually metastatic at the time of diagnosis, recent studies suggest that tumors require over 20 years to evolve from precancerous pancreatic intraepithelial neoplasia (PanIN) to invasive carcinoma (Yachida et al, 2010).

Methods

Results

Conclusion