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

• Published in: Cell reports (Cambridge) Vol. 14; no. 10; pp. 2325 - 2336
• Main Authors: Liou, Geou-Yarh, Döppler, Heike, DelGiorno, Kathleen E., Zhang, Lizhi, Leitges, Michael, Crawford, Howard C., Murphy, Michael P., Storz, Peter
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 15-03-2016; Elsevier
• Subjects: Acinar Cells - cytology; Acinar Cells - metabolism; ADAM17 Protein - metabolism; Animals; Cells, Cultured; Epidermal Growth Factor - metabolism; ErbB Receptors - metabolism; growth factor signaling; Humans; Kras; Ligands; Mice; mitochondria; Mitochondria - metabolism; Mutagenesis, Site-Directed; NF-kappa B p52 Subunit - metabolism; Oxidative Stress; pancreatic cancer; Pancreatic Neoplasms - metabolism; Pancreatic Neoplasms - pathology; PanIN; Precancerous Conditions; Protein Kinase C - metabolism; Proto-Oncogene Proteins p21(ras) - antagonists & inhibitors; Proto-Oncogene Proteins p21(ras) - genetics; Proto-Oncogene Proteins p21(ras) - metabolism; Reactive Oxygen Species - metabolism; RNA Interference; Signal Transduction; Up-Regulation; pancreatic cancer; Kras; growth factor signaling; mitochondria; oxidative stress; PanIN
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2016.02.029

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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•KRas-induced mROS initiates the dedifferentiation of pancreatic acinar cells•KRas/mROS signaling upregulates EGFR and its ligands via PKD1/NF-κB•The antioxidant MitoQ blocks the formation of pancreatic precancerous lesions
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.