Metastatic pancreatic cancer is dependent on oncogenic Kras in mice
Open accessAbstract
Pancreatic cancer is one of the deadliest human malignancies, and its prognosis has not improved over the past 40 years. Mouse models that spontaneously develop pancreatic adenocarcinoma and mimic the progression of the human disease are emerging as a new tool to investigate the basic biology of this disease and identify potential therapeutic targets. Here, we describe a new model of metastatic pancreatic adenocarcinoma based on pancreas-specific, inducible and reversible expression of an oncogenic form of Kras, together with pancreas-specific expression of a mutant form of the tumor suppressor p53. Using high-resolution magnetic resonance imaging to follow individual animals in longitudinal studies, we show that both primary and metastatic lesions depend on continuous Kras activity for their maintenance. However, re-activation of Kras* following prolonged inactivation leads to rapid tumor relapse, raising the concern that Kras*-resistance might eventually be acquired. Thus, our data identifies Kras* as a key oncogene in pancreatic cancer maintenance, but raises the possibility of acquired resistance should Kras inhibitors become available for use in pancreatic cancer.
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In inducible GEMMs, withdrawal of oncogenic Kras resulted in regression of invasive neoplasia, including metastatic disease.
“Withdrawal of oncogenic Kras resulted in regression of invasive neoplasia, including regression of metastatic disease63–65.”
From Pancreatic cancer: Advances and challenges (2023) · cites this paper as [65]
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- Authors
- Collins, M. A., Brisset, J.-C., Zhang, Y., Bednar, F., Pierre, J., Heist, K. A., Galbán, C. J., Galbán, S., & di Magliano, M. P.
- Affiliations
- University of Michigan (US)
- ORCID
- Venue
- PLoS ONE
- Publisher
- Public Library of Science (PLoS)
- Published
- 2012-12-03
- Volume
- 7
- Issue
- 12
- Pages
- e49707
- ISSN
- 1932-6203 (ISSN-L)
- PMC
- PMC3513322
- OpenAlex
- W2087523490
- Cited by
- 178
- References
- 38
- Citations by year
- 2026: 6 · 2025: 9 · 2024: 13 · 2023: 9 · 2022: 11 · 2021: 17 · 2020: 19 · 2019: 8 · 2018: 15 · 2017: 24 · 2016: 12 · 2015: 13 · 2014: 14 · 2013: 8
- FWCI
- 5.54
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- PLoS ONE (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- American College of Surgeons
- University of Michigan
- National Institutes of Health (NIH T32, NIH P50, 5-T32-HD007515)
- National Cancer Institute (NIH P50 CA093990, P50 CA93990, R01CA151588, P50CA130810, P50CA13810, P50CA093990)
- National Institute of General Medical Sciences (NIH T32 GM07315, T32GM007315)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development ((NIH T32 HD007505, 5-T32-HD007515, T32HD007505)
- 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
- metastatic pancreatic adenocarcinoma, oncogenic KRAS, KRAS, p53, mouse tumor model, tumor maintenance, tumor recurrence, KRAS inhibitor resistance
- MeSH terms
- Adenocarcinoma, Animals, Immunohistochemistry, Magnetic Resonance Imaging, Neoplasm Metastasis, Pancreatic Neoplasms, Genes, ras, Blotting, Western, Polymerase Chain Reaction, Mice
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