Abstract
miRNA levels are altered in pancreatic ductal adenocarcinoma (PDA), the most common and lethal pancreatic malignancy, and intact miRNA processing is essential for lineage specification during pancreatic development. However, the role of miRNA processing in PDA has not been explored. Here we study the role of miRNA biogenesis in PDA development by deleting the miRNA processing enzyme Dicer in a PDA mouse model driven by oncogenic Kras. We find that loss of Dicer accelerates Kras driven acinar dedifferentiation and acinar to ductal metaplasia (ADM), a process that has been shown to precede and promote the specification of PDA precursors. However, unconstrained ADM also displays high levels of apoptosis. Dicer loss does not accelerate development of Kras driven PDA precursors or PDA, but surprisingly, we observe that mouse PDA can develop without Dicer, although at the expense of proliferative capacity. Our data suggest that intact miRNA processing is involved in both constraining pro-tumorigenic changes in pancreatic differentiation as well as maintaining viability during PDA initiation.
Highlights
Pancreatic ductal adenocarcinoma (PDA) appears to develop through a series of ductal precursor lesions, including the most common type, pancreatic intraepithelial neoplasia (PanIN)
Evidence from mouse models suggests that mutant KrasG12D; Dicerflox/ flox (Kras) can contribute to PDA initiation by reprogramming acinar cells into a duct like lineage capable of becoming PanINs via a process termed acinar to ductal metaplasia (ADM) [4,5,6]
By deleting the miRNA-processing enzyme Dicer in a Kras driven mouse model of PDA, we find that miRNA processing regulates both differentiation and viability during Kras driven pancreatic transformation
Summary
Pancreatic ductal adenocarcinoma (PDA) appears to develop through a series of ductal precursor lesions, including the most common type, pancreatic intraepithelial neoplasia (PanIN) Both PanINs and PDA exhibit Kras mutations, which may be an initiating event. Evidence from mouse models suggests that mutant Kras can contribute to PDA initiation by reprogramming acinar cells into a duct like lineage capable of becoming PanINs via a process termed acinar to ductal metaplasia (ADM) [4,5,6]. This ability to change pancreatic plasticity may be an important step in PDA initiation, as acinar cells have been shown to be dramatically more sensitive to Kras dependent PanIN development compared to duct cells [7]. Since attempts at direct inhibition of oncogenic Kras have been generally unsuccessful[8], defining critical mediators of pro-tumorigenic differentiation and viability downstream of mutant Kras may represent alternative therapeutic approaches
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