title: Mutant KRas-Induced Mitochondrial Oxidative Stress in Acinar Cells Upregulates EGFR Signaling to Drive Formation of Pancreatic Precancerous Lesions.
abstract: 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.
authors.affiliation: Department of Cancer Biology, Mayo Clinic, Jacksonville, FL 32224, USA.
authors.forename: Geou-Yarh
authors.initials: GY
authors.lastname: Liou
authors.affiliation: Department of Cancer Biology, Mayo Clinic, Jacksonville, FL 32224, USA.
authors.forename: Heike
authors.initials: H
authors.lastname: Döppler
authors.affiliation: Department of Cancer Biology, Mayo Clinic, Jacksonville, FL 32224, USA; Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
authors.forename: Kathleen E
authors.initials: KE
authors.lastname: DelGiorno
authors.affiliation: Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN 55905, USA.
authors.forename: Lizhi
authors.initials: L
authors.lastname: Zhang
authors.affiliation: The Biotechnology Centre of Oslo, University of Oslo, 0349 Oslo, Norway.
authors.forename: Michael
authors.initials: M
authors.lastname: Leitges
authors.affiliation: Department of Cancer Biology, Mayo Clinic, Jacksonville, FL 32224, USA; Molecular and Integrative Physiology and Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Howard C
authors.initials: HC
authors.lastname: Crawford
authors.affiliation: MRC Mitochondrial Biology Unit, Wellcome Trust/MRC Building, Hills Road, Cambridge CB2 0XY, UK.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Murphy
authors.affiliation: Department of Cancer Biology, Mayo Clinic, Jacksonville, FL 32224, USA. Electronic address: storz.peter@mayo.edu.
authors.forename: Peter
authors.initials: P
authors.lastname: Storz
mesh_terms: D000072198:ADAM17 Protein / Q000378:metabolism; D061354:Acinar Cells / Q000166:cytology / Q000378:metabolism*; D000818:Animals; D002478:Cells, Cultured; D004815:Epidermal Growth Factor / Q000378:metabolism; D066246:ErbB Receptors / Q000378:metabolism*; D006801:Humans; D008024:Ligands; D051379:Mice; D008928:Mitochondria / Q000378:metabolism*; D016297:Mutagenesis, Site-Directed; D052003:NF-kappa B p52 Subunit / Q000378:metabolism; D018384:Oxidative Stress; D010190:Pancreatic Neoplasms / Q000378:metabolism / Q000473:pathology; D011230:Precancerous Conditions; D011493:Protein Kinase C / Q000378:metabolism; D016283:Proto-Oncogene Proteins p21(ras) / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction; D015854:Up-Regulation
chemical_list: D008024:Ligands; D052003:NF-kappa B p52 Subunit; D017382:Reactive Oxygen Species; D004815:Epidermal Growth Factor; C089212:protein kinase D; C541485:EGFR protein, mouse; D066246:ErbB Receptors; D011493:Protein Kinase C; D000072198:ADAM17 Protein; C495971:Hras protein, mouse; D016283:Proto-Oncogene Proteins p21(ras)
keywords: Kras; PanIN; growth factor signaling; mitochondria; oxidative stress; pancreatic cancer