<i>Dicer</i> Is Required for Maintenance of Adult Pancreatic Acinar Cell Identity and Plays a Role in Kras-Driven Pancreatic Neoplasia

<div><p>The role of miRNA processing in the maintenance of adult pancreatic acinar cell identity and during the initiation and progression of pancreatic neoplasia has not been studied in detail. In this work, we deleted <i>Dicer</i> specifically in adult pancreatic acinar cells, with or without simultaneous activation of oncogenic Kras. We found that <i>Dicer</i> is essential for the maintenance of acinar cell identity. Acinar cells lacking <i>Dicer</i> showed increased plasticity, as evidenced by loss of polarity, initiation of epithelial-to-mesenchymal transition (EMT) and acinar-to-ductal metaplasia (ADM). In the context of oncogenic Kras activation, the initiation of ADM and pancreatic intraepithelial neoplasia (PanIN) were both highly sensitive to <i>Dicer</i> gene dosage. Homozygous <i>Dicer</i> deletion accelerated the formation of ADM but not PanIN. In contrast, heterozygous <i>Dicer</i> deletion accelerated PanIN initiation, revealing complex roles for <i>Dicer</i> in the regulation of both normal and neoplastic pancreatic epithelial identity.</p></div

Deletion of <i>Dicer</i> induces loss of polarity in acinar cells following Dicer deletion.

<p>(A) Epithelial cell polarity marker CD49f (white) is expressed basally, while phalloidin labeling (red) is observed apically in control <i>Mist-Cre^ERT2; LSL-YFP; Dicer^wt/wt</i> pancreas following tamoxifen treatment. (B) In the <i>Mist-Cre^ERT2; LSL-YFP; Dicer^fl/fl</i> mice, <i>Dicer</i> deletion leads to translocation of CD49f in the lateral membrane, and loss of apical phalloidin labeling. Cytoplasmic expression of YFP is shown in green as a surrogate marker of Cre-mediated recombination. Nuclei are stained with DAPI (blue).</p