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) signaling, cells that underwent ADM can progress to pancreatic intraepithelial lesions (PanINs) 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 signaling 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.

Positive cross talk between protein kinase D and β-catenin in intestinal epithelial cells: impact on β-catenin nuclear localization and phosphorylation at Ser552

“…New recurrent PRKD1 gene rearrangements and variant fusions have been found in cribriform adenocarcinoma of the oropharynx (71). PKD1 has been proposed as a therapeutic target in pancreatic (15,31,37) and colon (69) cancers, although a different conclusion has also been presented (57). It is conceivable that the PKD/␤-catenin cross talk identified here contributes to the mechanism(s) by which PKDs promote malignant transformation of epithelial cells, but further systematic studies are needed to prove this hypothesis.…”

Acinar cell plasticity and development of pancreatic ductal adenocarcinoma

“…During mouse and zebrafish pancreas development, expression of Notch1 intracellular domain (NICD; activated Notch1) prevents differentiation of pancreatic acinar cells and endocrine and exocrine development, indicating that it functions to maintain the undifferentiated state of pancreatic precursor cells 65,66 . In mice, Notch can be activated downstream of both EGFR–KRAS signalling and oncogenic KRAS activation to drive acinar cell dedifferentiation into a duct-like progenitor phenotype 9,64,67 , but its activation is not sufficient to drive progression of preneoplastic lesions to invasive adenocarcinoma 64 . Furthermore, NICD induces SOX9 expression 68 , but SOX9 function is also required for maintaining Notch signalling 69 , indicating a mechanism for signal amplification.…”

“…The implication of ADM in the development of pancreatic adenocarcinoma was first demonstrated in mice by transgenic overexpression of transforming growth factor (TGF)-α 8 . ADM was also demonstrated in vitro in 3D cell culture, in which mouse acinar cell clusters, in the presence of internal or external stress signalling, oncogenic KRAS, inflammatory cytokines or growth factors that activate epidermal growth factor receptor (EGFR), spontaneously transdifferentiate into duct-like structures 4,6,9–11 . Similar 3D cell culture experiments showed that ADM in human acinar cells can be induced by TGFβ 12 .…”

KRas, ROS and the initiation of pancreatic cancer

“…These include activation of the ERK1/2 signaling pathway, 6 upregulation of epidermal growth factor receptor (EGF-R) signaling, 5 as well as induction of canonical and alternative activation pathways for nuclear factor k-B (NF-kB), 5 which both have been implicated in the progression of PDA. 20,21 The serine/threonine kinase Protein Kinase D1 (PKD1) is a major mediator of KRas-mROS signaling, 5,22 however, its activation by mROS most likely is indirect. Previously, it was shown that in response to mROS PKD1 can be activated via Src-mediated phosphorylation events.…”

“…[30][31][32] An emerging key-role of PKD1 for the initiation of pancreatic cancer is indicated by its additional involvement in the activation of Notch signaling downstream of mutant and wildtype KRas. 22,33 Notch and NF-kB signaling pathways can co-operate to mediate formation of pre-neoplastic lesions. 34 Thus PKD1 brings together 2 important pathways that drive the formation of precancerous lesions.…”