Mutant KRas-Induced Mitochondrial Oxidative Stress in Acinar Cells Upregulates EGFR Signaling to Drive Formation of Pancreatic Precancerous Lesions

Publication date: Available online 3 March 2016
Source:Cell Reports
Author(s): Geou-Yarh Liou, Heike Döppler, Kathleen E. DelGiorno, Lizhi Zhang, Michael Leitges, Howard C. Crawford, Michael P. Murphy, Peter Storz
The development of pancreatic cancer requires the acquisition of oncogenic KRas mutations and upregulation of growth factor signaling, but the relationship between these is not well established. Here, we show that mutant KRas alters mitochondrial metabolism in pancreatic acinar cells, resulting in increased generation of mitochondrial reactive oxygen species (mROS). Mitochondrial ROS then drives the dedifferentiation of acinar cells to a duct-like progenitor phenotype and progression to PanIN. This is mediated via the ROS-receptive kinase protein kinase D1 and the transcription factors NF-κB1 and NF-κB2, which upregulate expression of the epidermal growth factor, its ligands, and their sheddase ADAM17. In vivo, interception of KRas-mediated generation of mROS reduced the formation of pre-neoplastic lesions. Hence, our data provide insight into how oncogenic KRas interacts with growth factor signaling to induce the formation of pancreatic cancer.

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Teaser

Liou et al. show that acquisition of an activating KRas mutation initiates the dedifferentiation of pancreatic acinar cells through generation of mitochondrial oxidative stress and activation of the PKD1/NF-κB pathway. This leads to autocrine EGFR signaling, resulting in the formation of duct-like progenitor cells and development of precancerous lesions.


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