TGF-β1 promotes acinar to ductal metaplasia of human pancreatic acinar cells.

Jun Liu,Chengyang Liu,Glenn A Halff,Ali Naji,Naoki Akanuma,Pei Wang,Luzhe Sun,William K Washburn

doi:10.1038/srep30904

Abstract

Animal studies suggest that pancreatitis-induced acinar-to-ductal metaplasia (ADM) is a key event for pancreatic ductal adenocarcinoma (PDAC) initiation. However, there has not been an adequate system to explore the mechanisms of human ADM induction. We have developed a flow cytometry-based, high resolution lineage tracing method and 3D culture system to analyse ADM in human cells. In this system, well-known mouse ADM inducers did not promote ADM in human cells. In contrast, TGF-β1 efficiently converted human acinar cells to duct-like cells (AD) in a SMAD-dependent manner, highlighting fundamental differences between the species. Functionally, AD cells gained transient proliferative capacity. Furthermore, oncogenic KRAS did not induce acinar cell proliferation, but did sustain the proliferation of AD cells, suggesting that oncogenic KRAS requires ADM-associated-changes to promote PDAC initiation. This ADM model provides a novel platform to explore the mechanisms involved in the development of human pancreatic diseases.

Highlights

Animal studies suggest that pancreatitis-induced acinar-to-ductal metaplasia (ADM) is a key event for pancreatic ductal adenocarcinoma (PDAC) initiation
Lineage tracing experiments in mouse Pancreatic ductal adenocarcinoma (PDAC) models demonstrated that pancreatic intraepithelial neoplasia (PanINs) lesions are mainly derived from acinar cells undergoing acinar to ductal metaplasia (ADM), an event usually induced by pancreatitis[1,7,8], suggesting that ADM might be an early event that promotes KRAS-driven PDAC tumourigenesis[1,9]
To confirm whether Ulex europaeus agglutinin 1 (UEA-1) can bind to acinar cells, exocrine pancreatic cells labelled with fluorescein isothiocyanate (FITC)-UEA-1 were further stained with the ductal cell marker CD13321 and the acinar cell marker HPX122, and analysed by flow cytometry

Summary

Introduction

Animal studies suggest that pancreatitis-induced acinar-to-ductal metaplasia (ADM) is a key event for pancreatic ductal adenocarcinoma (PDAC) initiation. Lineage tracing experiments in mouse PDAC models demonstrated that PanIN lesions are mainly derived from acinar cells undergoing acinar to ductal metaplasia (ADM), an event usually induced by pancreatitis[1,7,8], suggesting that ADM might be an early event that promotes KRAS-driven PDAC tumourigenesis[1,9]. Supporting this view, pancreatitis is the biggest risk factor for PDAC in humans[10], and experimental pancreatitis is required for KRAS-driven PDAC initiation in adult mice[11,12]. Our study highlights the different signals required by human and mouse cells to induce ADM, but this new system provide a platform to investigate the initiation of PDAC tumourigenesis in human cells

Methods

Results

Conclusion