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Preinvasive and invasive ductal pancreatic cancer and its early detection in the mouse
Open accessAbstract
To evaluate the role of oncogenic RAS mutations in pancreatic tumorigenesis, we directed endogenous expression of KRAS(G12D) to progenitor cells of the mouse pancreas. We find that physiological levels of Kras(G12D) induce ductal lesions that recapitulate the full spectrum of human pancreatic intraepithelial neoplasias (PanINs), putative precursors to invasive pancreatic cancer. The PanINs are highly proliferative, show evidence of histological progression, and activate signaling pathways normally quiescent in ductal epithelium, suggesting potential therapeutic and chemopreventive targets for the cognate human condition. At low frequency, these lesions also progress spontaneously to invasive and metastatic adenocarcinomas, establishing PanINs as definitive precursors to the invasive disease. Finally, mice with PanINs have an identifiable serum proteomic signature, suggesting a means of detecting the preinvasive state in patients.
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“Expression of mutant Kras alone from embryonic pancreatic cells results in PanIN with histological and molecular features that resemble PanIN in human PDACs (72).”
From KRAS mutation in pancreatic cancer (2021) · cites this paper as [72]
In the citing paper
“conditional expression of oncogenic mutant Kras in the pancreas, using Cre-recombinase driven by pancreatic transcription factor promoters activated during embryonic development, leads to development of murine PanIN lesions histologically reminiscent of human disease28.”
From Pancreatic cancer: Advances and challenges (2023) · cites this paper as [28]
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Metadata
- Authors
- Hingorani, S. R., Petricoin, E. F., Maitra, A., Rajapakse, V., King, C., Jacobetz, M. A., Ross, S., Conrads, T. P., Veenstra, T. D., Hitt, B. A., Kawaguchi, Y., Johann, D., Liotta, L. A., Crawford, H. C., Putt, M. E., Jacks, T., Wright, C. V. E., Hruban, R. H., Lowy, A. M., & Tuveson, D. A.
- Affiliations
- Abramson Cancer Center (US)
- Center for Biologics Evaluation and Research (US)
- Johns Hopkins University (US)
- National Cancer Institute (US)
- Vanderbilt University (US)
- State University of New York (US)
- University of Pennsylvania (US)
- Howard Hughes Medical Institute (US)
- University of Cincinnati (US)
- Corresponding author
- Tuveson, David A.
- ORCID
- Venue
- Cancer Cell
- Publisher
- Elsevier BV
- Published
- 2003-12
- Volume
- 4
- Issue
- 6
- Pages
- 437-450
- ISSN
- 1535-6108 (ISSN-L)
- OpenAlex
- W2066135299
- Cited by
- 2,471
- References
- 62
- Citations by year
- 2026: 75 · 2025: 112 · 2024: 106 · 2023: 137 · 2022: 132 · 2021: 141 · 2020: 156 · 2019: 143 · 2018: 145 · 2017: 148 · 2016: 142 · 2015: 140 · 2014: 145 · 2013: 138 · 2012: 102
- FWCI
- 18.85
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cancer Cell (publishedVersion)
- PubMed (publishedVersion)
- DigitalCommons-Cedarville (Cedarville University) (submittedVersion)
- Funders
- National Cancer Institute (R25-CA87812, P50CA-62924, R25CA087812, P50CA062924)
- National Institute of Diabetes and Digestive and Kidney Diseases (P30DK050306)
- Topics
- Health Sciences › Medicine › Oncology › Pancreatic and Hepatic Oncology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Pancreatic function and diabetes
- Keywords
- pancreatic ductal adenocarcinoma, pancreatic intraepithelial neoplasia, KRAS G12D, oncogenic Ras mutations, pancreatic progenitor cells, pancreatic carcinogenesis, metastatic adenocarcinoma, early cancer detection, chemoprevention, mouse model
- MeSH terms
- Transcription Factor HES-1, Animals, Humans, Immunohistochemistry, Isoenzymes, Membrane Proteins, Mutation, Neoplasm Metastasis, Neoplasm Staging, Pancreas, Pancreatic Neoplasms, Prostaglandin-Endoperoxide Synthases, Genes, ras, Homeodomain Proteins, Matrix Metalloproteinase 7, Carcinoma, Pancreatic Ductal, Mice, Cyclooxygenase 2, Basic Helix-Loop-Helix Proteins
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