@article{27a84e52d9d346959573bf1a5a58fd43,
title = "Protein kinase D1 drives pancreatic acinar cell reprogramming and progression to intraepithelial neoplasia",
abstract = "The transdifferentiation of pancreatic acinar cells to a ductal phenotype (acinar-to-ductal metaplasia, ADM) occurs after injury or inflammation of the pancreas and is a reversible process. However, in the presence of activating Kras mutations or persistent epidermal growth factor receptor (EGF-R) signalling, cells that underwent ADM can progress to pancreatic intraepithelial neoplasia (PanIN) and eventually pancreatic cancer. In transgenic animal models, ADM and PanINs are initiated by high-affinity ligands for EGF-R or activating Kras mutations, but the underlying signalling mechanisms are not well understood. Here, using a conditional knockout approach, we show that protein kinase D1 (PKD1) is sufficient to drive the reprogramming process to a ductal phenotype and progression to PanINs. Moreover, using 3D explant culture of primary pancreatic acinar cells, we show that PKD1 acts downstream of TGFα and Kras, to mediate formation of ductal structures through activation of the Notch pathway.",
author = "Liou, {Geou Yarh} and Heike D{\"o}ppler and Braun, {Ursula B.} and Richard Panayiotou and {Scotti Buzhardt}, Michele and Radisky, {Derek C.} and Crawford, {Howard C.} and Fields, {Alan P.} and Murray, {Nicole R.} and Wang, {Q. Jane} and Michael Leitges and Peter Storz",
note = "Funding Information: We thank our colleagues in the Storz laboratory for helpful discussions. We also thank Brandy H. Edenfield (Cancer Biology Histology Facility) for IHC. This work was supported by grants from the AACR (08-20-25-STOR), the NIH (CA135102, GM86435 and CA140182) and a Pilot Project from the Mayo Clinic SPORE for Pancreatic Cancer (P50CA102701)—all to P.S., a grant from the Norwegian Research Council (grant: 197261) to M.L., as well as CA122086 (D.C.R.), CA142580 (Q.J.W.), CA136754 (H.C.C.), CA140290 (N.R.M.) and CA081436 (A.P.F.). We thank the Pancreatic Cancer Action Network (PanCAN) and the Boshell Foundation for their support. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Cancer Institute or the National Institutes of Health. The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript.",
year = "2015",
month = feb,
day = "20",
doi = "10.1038/ncomms7200",
language = "English (US)",
volume = "6",
journal = "Nature Communications",
issn = "2041-1723",
publisher = "Nature Publishing Group",
}