Protein kinase D1 drives pancreatic acinar cell reprogramming and progression to intraepithelial neoplasia

Geou-Yarh Liou, Heike Döppler, Ursula B. Braun, Richard Panayiotou, Michele Scotti Buzhardt, Derek C. Radisky, Howard C. Crawford, Alan P. Fields, Nicole R. Murray, Q. Jane Wang, Michael Leitges () and Peter Storz ()
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Geou-Yarh Liou: Mayo Clinic Comprehensive Cancer Center, Mayo Clinic
Heike Döppler: Mayo Clinic Comprehensive Cancer Center, Mayo Clinic
Ursula B. Braun: The Biotechnology Centre of Oslo, University of Oslo
Richard Panayiotou: Mayo Clinic Comprehensive Cancer Center, Mayo Clinic
Michele Scotti Buzhardt: Mayo Clinic Comprehensive Cancer Center, Mayo Clinic
Derek C. Radisky: Mayo Clinic Comprehensive Cancer Center, Mayo Clinic
Howard C. Crawford: Mayo Clinic Comprehensive Cancer Center, Mayo Clinic
Alan P. Fields: Mayo Clinic Comprehensive Cancer Center, Mayo Clinic
Nicole R. Murray: Mayo Clinic Comprehensive Cancer Center, Mayo Clinic
Q. Jane Wang: University of Pittsburgh
Michael Leitges: The Biotechnology Centre of Oslo, University of Oslo
Peter Storz: Mayo Clinic Comprehensive Cancer Center, Mayo Clinic

Nature Communications, 2015, vol. 6, issue 1, 1-11

Abstract: 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.

Date: 2015
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DOI: 10.1038/ncomms7200

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