Abstract A63: Human pancreatic cells have distinct aspects in induction of acinar to ductal metaplasia

Abstract

Abstract Multiple animal studies suggest that pancreatitis-induced acinar-to-ductal metaplasia (ADM) is a key event for the initiation of pancreatic ductal adenocarcinoma (PDAC) tumorigenesis. However, until now, there has not been an adequate system to explore the mechanisms of ADM induction in humans. To address this problem, we have developed a flow cytometry-based, high resolution lineage tracing method to analyse ADM in primary human cells. Using a set of cell surface markers, we have successfully defined and purified human acinar, ductal and acinar-to-ductal transdifferentiated (AD) cells. A Matrigel-based 3D culture system which suppresses spontaneous ADM was developed to identify ADM inducers of primary human acinar cells. In contrast to the effect in mouse acinar cells, TGF-β1 efficiently converted human acinar cells to AD cells in a SMAD-dependent manner. Consistently, phospho-SMAD3 (p-SMAD3) expression was significantly increased in acinar cells from human pancreatitis samples, supporting an important role of the TGF-β/SMAD axis for human ADM in vivo. Furthermore, all known inducers of ADM in mice did not promote ADM in human cells, highlighting fundamental differences between the species. Capitalizing on our ability to separate different cell populations for functional analysis, we found that AD cells gained transient proliferative capacity. More interestingly, while oncogenic KRAS did not induce acinar cell proliferation, it did sustain 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. Grant Support: Support received from the Cancer Prevention and Research Institute of Texas (P. Wang). Jun Liu received support by way of the training grant (RP140105) from the Cancer Prevention and Research Institute of Texas. Citation Format: Jun Liu, Naoki Akanuma, Luzhe Sun, Pei Wang.{Authors}. Human pancreatic cells have distinct aspects in induction of acinar to ductal metaplasia. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2016 May 12-15; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2016;76(24 Suppl):Abstract nr A63.