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.
| Original language | English (US) |
|---|---|
| Article number | 6200 |
| Journal | Nature Communications |
| Volume | 6 |
| DOIs | |
| State | Published - Feb 20 2015 |
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ASJC Scopus subject areas
- Biochemistry, Genetics and Molecular Biology(all)
- Chemistry(all)
- Physics and Astronomy(all)
Cite this
Protein kinase D1 drives pancreatic acinar cell reprogramming and progression to intraepithelial neoplasia. / Liou, Geou Yarh; Döppler, Heike; Braun, Ursula B.; Panayiotou, Richard; Scotti Buzhardt, Michele; Radisky, Derek C; Crawford, Howard C.; Fields, Alan P; Murray, Nicole R; Wang, Q. Jane; Leitges, Michael; Storz, Peter.
In: Nature Communications, Vol. 6, 6200, 20.02.2015.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Protein kinase D1 drives pancreatic acinar cell reprogramming and progression to intraepithelial neoplasia
AU - Liou, Geou Yarh
AU - Döppler, Heike
AU - Braun, Ursula B.
AU - Panayiotou, Richard
AU - Scotti Buzhardt, Michele
AU - Radisky, Derek C
AU - Crawford, Howard C.
AU - Fields, Alan P
AU - Murray, Nicole R
AU - Wang, Q. Jane
AU - Leitges, Michael
AU - Storz, Peter
PY - 2015/2/20
Y1 - 2015/2/20
N2 - 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.
AB - 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.
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U2 - 10.1038/ncomms7200
DO - 10.1038/ncomms7200
M3 - Article
C2 - 25698580
AN - SCOPUS:84923323788
VL - 6
JO - Nature Communications
JF - Nature Communications
SN - 2041-1723
M1 - 6200
ER -