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MAPK Signaling Is Required for Dedifferentiation of Acinar Cells and Development of Pancreatic Intraepithelial Neoplasia in Mice
Open accessAbstract
Background & aims Kras signaling via mitogen-activated protein kinase (MAPK) is highly up-regulated in pancreatic cancer cells. We investigated whether MAPK signaling is required for the initiation and maintenance of pancreatic carcinogenesis in mice.Methods We studied the formation and maintenance of pancreatic intraepithelial neoplasia (PanINs) in p48Cre; TetO-KrasG12D; Rosa26(rtTa-IRES-EGFP) (iKras*) mice and LSL-KrasG12D mice bred with p48Cre mice (KC). Mice were given oral PD325901, a small-molecule inhibitor of MEK1 and MEK2 (factors in the MAPK signaling pathway), along with injections of cerulein to induce pancreatitis. Other mice were given PD325901 only after PanINs developed. Pancreatic tissues were collected and evaluated using histologic, immunohistochemical, immunofluorescence, and electron microscopy analyses. Acinar cells were isolated from the tissues and the effects of MEK1 and 2 inhibitors were assessed.Results PD325901 prevented PanIN formation, but not pancreatitis, in iKras* and KC mice. In iKras* or KC mice given PD325901 at 5 weeks after PanINs developed, PanINs regressed and acinar tissue regenerated. The regression occurred through differentiation of the PanIN cells to acini, accompanied by re-expression of the acinar transcription factor Mist1.Conclusions In iKras* and KC mice, MAPK signaling is required for the initiation and maintenance of pancreatic cancer precursor lesions. MAPK signaling promotes formation of PanINs by enabling dedifferentiation of acinar cells into duct-like cells that are susceptible to transformation.
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“in such an inducible system, PanINs can be observed to re-differentiate back to acinar cells in the absence of tumor suppressor loss66.”
From Pancreatic cancer: Advances and challenges (2023) · cites this paper as [66]
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“These cultures are known to mimic acinar to ductal metaplasia (35), the proposed first step of PDAC tumorigenesis (36).”
Background
Metadata
- Authors
- Collins, M. A., Yan, W., Sebolt–Leopold, J. S., & Pasca di Magliano, M.
- Affiliations
- University of Michigan (US)
- ORCID
- Yan, Wei
- Venue
- Gastroenterology
- Publisher
- Elsevier BV
- Published
- 2014-03
- Volume
- 146
- Issue
- 3
- Pages
- 822-834.e7
- ISSN
- 0016-5085 (ISSN-L)
- PMC
- PMC4037403
- OpenAlex
- W2010171965
- Cited by
- 133
- References
- 46
- Citations by year
- 2026: 7 · 2025: 8 · 2024: 8 · 2023: 19 · 2022: 12 · 2021: 11 · 2020: 15 · 2019: 6 · 2018: 14 · 2017: 11 · 2016: 8 · 2015: 11 · 2014: 3
- FWCI
- 4.11
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Gastroenterology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Cancer Institute (R01CA151588, P50CA130810, R01CA155198, P50CA13810)
- National Institute of General Medical Sciences (T32GM07315, T32GM007315)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (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 › Endocrinology, Diabetes and Metabolism › Pancreatic function and diabetes
- Keywords
- MAPK signaling, pancreatic intraepithelial neoplasia, KRAS G12D, pancreatic carcinogenesis, MEK1/2 inhibition, pancreatitis, Mist1, pancreatic cancer precursor lesions
- MeSH terms
- Animals, Carcinoma in Situ, Disease Models, Animal, Female, Male, Mice, Mutant Strains, Pancreatic Neoplasms, Pancreatitis, Signal Transduction, Up-Regulation, Mitogen-Activated Protein Kinase Kinases, MAP Kinase Signaling System, MAP Kinase Kinase 1, MAP Kinase Kinase 2, Mice, Cell Dedifferentiation, Acinar Cells
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