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, Peter Storz

Research output: Contribution to journalArticle

35 Citations (Scopus)

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 languageEnglish (US)
Article number6200
JournalNature Communications
Volume6
DOIs
StatePublished - Feb 20 2015

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Acinar Cells
Metaplasia
Epidermal Growth Factor Receptor
progressions
Protein Kinases
phenotype
mutations
Cell signaling
proteins
cells
Phenotype
pancreas
Neoplasms
Mutation
Genetically Modified Animals
Animals
animal models
Chemical activation
notches
Ligands

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 journalArticle

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. / Protein kinase D1 drives pancreatic acinar cell reprogramming and progression to intraepithelial neoplasia. In: Nature Communications. 2015 ; Vol. 6.
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