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.

journal_name

Nat Commun

journal_title

Nature communications

authors

Liou GY,Döppler H,Braun UB,Panayiotou R,Scotti Buzhardt M,Radisky DC,Crawford HC,Fields AP,Murray NR,Wang QJ,Leitges M,Storz P

doi

10.1038/ncomms7200

subject

Has Abstract

pub_date

2015-02-20 00:00:00

pages

6200

issn

2041-1723

pii

ncomms7200

journal_volume

6

pub_type

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