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
Department of Cancer Biology, Mayo Clinic Comprehensive Cancer Center, Mayo Clinic, Jacksonville, Florida 32224, USA.
The Biotechnology Centre of Oslo, University of Oslo, N-0349 Oslo, Norway.
Nat Commun. 2015 Feb 20;6:6200. doi: 10.1038/ncomms7200.
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.
胰腺腺泡细胞向导管表型的转分化（腺泡-导管化生，ADM）发生在胰腺损伤或炎症后，是一个可逆过程。然而，在存在激活的Kras突变或持续的表皮生长因子受体（EGF-R）信号传导的情况下，经历ADM的细胞可进展为胰腺上皮内瘤变（PanIN）并最终发展为胰腺癌。在转基因动物模型中，ADM和PanIN由EGF-R的高亲和力配体或激活的Kras突变引发，但潜在的信号传导机制尚不清楚。在这里，我们使用条件性敲除方法表明，蛋白激酶D1（PKD1）足以驱动重编程过程向导管表型发展并进展为PanIN。此外，利用原代胰腺腺泡细胞的三维外植体培养，我们表明PKD1在TGFα和Kras的下游起作用，通过激活Notch途径介导导管结构的形成。
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