Mutant KRas-Induced Mitochondrial Oxidative Stress in Acinar Cells Upregulates EGFR Signaling to Drive Formation of Pancreatic Precancerous Lesions
Open accessAbstract
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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In mice, metabolic reprogramming in response to oncogenic KRas in pancreatic acinar cells promotes acinar-to-ductal metaplasia, a precursor to pancreatic ductal adenocarcinoma.
“In mice, metabolic reprogramming in response to oncogenic KRas in pancreatic acinar cells promotes acinar-to-ductal metaplasia (ADM), a precursor to pancreatic ductal adenocarcinoma (PDAC) (19).”
From Metabolic reprogramming and cancer progression (2020) · cites this paper as [19]
Oncogenic KRas increases acetyl-CoA and ROS before ADM develops, and inhibiting these phenotypes blocks ADM.
“Oncogenic KRas increases the levels of acetyl coenzyme A (CoA) and reactive oxygen species (ROS) before the development of ADM, and inhibiting these phenotypes blocks ADM (19, 20).”
From Metabolic reprogramming and cancer progression (2020) · cites this paper as [19]
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- Authors
- Liou, G.-Y., Döppler, H., DelGiorno, K. E., Zhang, L., Leitges, M., Crawford, H. C., Murphy, M. P., & Storz, P.
- Affiliations
- Mayo Clinic (US)
- University of Oslo (NO)
- MRC Mitochondrial Biology Unit (GB)
- ORCID
- Venue
- Cell Reports
- Publisher
- Elsevier BV
- Published
- 2016-03
- Volume
- 14
- Issue
- 10
- Pages
- 2325-2336
- ISSN
- 2211-1247 (ISSN-L)
- PMC
- PMC4794374
- OpenAlex
- W2291790203
- Cited by
- 270
- References
- 44
- Citations by year
- 2026: 19 · 2025: 24 · 2024: 22 · 2023: 36 · 2022: 41 · 2021: 34 · 2020: 30 · 2019: 20 · 2018: 13 · 2017: 22 · 2016: 9
- FWCI
- 11.51
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Cell Reports (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Norges Forskningsråd
- National Institutes of Health (197261, CA140182, CA159222, CA200572)
- Topics
- Health Sciences › Medicine › Oncology › Pancreatic and Hepatic Oncology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Health Sciences › Medicine › Surgery › Pancreatitis Pathology and Treatment
- Keywords
- mutant KRAS, mitochondrial reactive oxygen species, mitochondrial oxidative stress, pancreatic acinar cells, EGFR signaling, pancreatic intraepithelial neoplasia, pancreatic precancerous lesions, protein kinase D1, NFKB1, NF-κB2, ADAM17, pancreatic cancer initiation, mitochondrial metabolism
- MeSH terms
- ADAM17 Protein, Animals, Cells, Cultured, Epidermal Growth Factor, Humans, Ligands, Mitochondria, Pancreatic Neoplasms, Precancerous Conditions, Protein Kinase C, Signal Transduction, Up-Regulation, Proto-Oncogene Proteins p21(ras), Mutagenesis, Site-Directed, Reactive Oxygen Species, Oxidative Stress, RNA Interference, Mice, NF-kappa B p52 Subunit, Acinar Cells, ErbB Receptors
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