Differential Cell Susceptibilities to Kras in the Setting of Obstructive Chronic Pancreatitis
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BACKGROUND & AIMS: Activating mutation of the KRAS gene is common in some cancers, such as pancreatic cancer, but rare in other cancers. Chronic pancreatitis is a predisposing condition for pancreatic ductal adenocarcinoma (PDAC), but how it synergizes with KRAS mutation is not known. METHODS: We used a mouse model to express an activating mutation of Kras in conjunction with obstruction of the main pancreatic duct to recapitulate a common etiology of human chronic pancreatitis. Because the cell of origin of PDAC is not clear, Kras mutation was introduced into either duct cells or acinar cells. RESULTS: expression in both cell types was protective against damage-associated cell death, chronic pancreatitis induced p53, p21, and growth arrest only in acinar-derived cells. Mutant duct cells did not elevate p53 or p21 expression and exhibited increased proliferation driving the appearance of PDAC over time. CONCLUSIONS: -initiated tumorigenesis is whether they undergo a p53-mediated damage response. In summary, we have uncovered a mechanism by which inflammation and intrinsic cellular programming synergize for the development of PDAC.
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Induction of pancreatic damage by pancreatic ductal ligation is sufficient to promote KRAS-mediated ductal-lineage tumorigenesis.
“the induction of pancreatic damage by pancreatic ductal ligation is sufficient to promote KRAS-mediated ductal-lineage tumorigenesis128.”
From Pancreatic cancer: Advances and challenges (2023) · cites this paper as [128]
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- Authors
- Shi, C., Pan, F. C., Kim, J. N., Washington, M. K., Padmanabhan, C., Meyer, C. T., Kopp, J. L., Sander, M., Gannon, M., Beauchamp, R. D., Wright, C. V., & Means, A. L.
- Affiliations
- Vanderbilt University Medical Center (US)
- University of California San Diego (US)
- VA Tennessee Valley Healthcare System (US)
- Corresponding author
- Means, Anna L.
- ORCID
- Venue
- Cellular and Molecular Gastroenterology and Hepatology
- Publisher
- Elsevier BV
- Published
- 2019
- Volume
- 8
- Issue
- 4
- Pages
- 579-594
- ISSN
- 2352-345X (ISSN-L)
- PMC
- PMC6889613
- OpenAlex
- W2958380790
- Cited by
- 21
- References
- 43
- Citations by year
- 2026: 1 · 2025: 4 · 2024: 2 · 2023: 2 · 2022: 1 · 2021: 6 · 2020: 4 · 2019: 1
- FWCI
- 1.25
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Cellular and Molecular Gastroenterology and Hepatology (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- MDC Repository (Max-Delbrueck-Center for Molecular Medicine) (acceptedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- eScholarship (California Digital Library) (submittedVersion, cc-by-nc-nd)
- Funders
- NIH (R21CA123061, P50CA095103, P30DK058404, R01DK105689, F32CA136124, P30CA068485)
- JDRF (U01DK072473, R01DK078803, R21CA194839)
- VA (1I01BX003744-01)
- Vanderbilt-Ingram Cancer Center (P30CA068485)
- Vanderbilt Digestive Diseases Research Center (P30DK08404)
- Topics
- Health Sciences › Medicine › Oncology › Pancreatic and Hepatic Oncology Research
- Health Sciences › Medicine › Surgery › Pancreatitis Pathology and Treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Keywords
- KRAS mutation, chronic pancreatitis, pancreatic ductal adenocarcinoma, pancreatic duct obstruction, acinar cells, duct cells, p53, p21, cell of origin, inflammation-driven tumorigenesis, mouse model
- MeSH terms
- Animals, Cell Transformation, Neoplastic, Disease Models, Animal, Metaplasia, Mutation, Pancreatic Neoplasms, Precancerous Conditions, Genes, ras, Signal Transduction, Proto-Oncogene Proteins p21(ras), Carcinoma, Pancreatic Ductal, Pancreatitis, Chronic, Mice, Acinar Cells, Carcinogenesis
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