Pancreatic epithelial plasticity mediated by acinar cell transdifferentiation and generation of nestin-positive intermediates
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Epithelial metaplasia occurs when one predominant cell type in a tissue is replaced by another, and is frequently associated with an increased risk of subsequent neoplasia. In both mouse and human pancreas, acinar-to-ductal metaplasia has been implicated in the generation of cancer precursors. We show that pancreatic epithelial explants undergo spontaneous acinar-to-ductal metaplasia in response to EGFR signaling, and that this change in epithelial character is associated with the appearance of nestin-positive transitional cells. Lineage tracing involving Cre/lox-mediated genetic cell labeling reveals that acinar-to-ductal metaplasia represents a true transdifferentiation event, mediated by initial dedifferentiation of mature exocrine cells to generate a population of nestin-positive precursors, similar to those observed during early pancreatic development. These results demonstrate that a latent precursor potential resides within mature exocrine cells, and that this potential is regulated by EGF receptor signaling. In addition, these observations provide a novel example of rigorously documented transdifferentiation within mature mammalian epithelium, and suggest that plasticity of mature cell types may play a role in the generation of neoplastic precursors.
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In mice, adult acinar cells can de-differentiate to a progenitor-like state with ductal appearance, termed acinar-to-ductal metaplasia (ADM).
“murine acinar cells can de-differentiate to a progenitor-like state with a ductal appearance. This has been termed acinar-to-ductal-metaplasia (ADM)110,111”
From Pancreatic cancer: Advances and challenges (2023) · cites this paper as [110]
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Self-citation
- Authors
- Means, A. L., Meszoely, I. M., Suzuki, K., Miyamoto, Y., Rustgi, A. K., Coffey, R. J., Wright, C. V. E., Stoffers, D. A., & Leach, S. D.
- Affiliations
- Vanderbilt University (US)
- Johns Hopkins University (US)
- Abramson Cancer Center (US)
- University of Pennsylvania (US)
- Corresponding author
- Leach, Steven D.
- ORCID
- Venue
- Development
- Publisher
- The Company of Biologists
- Published
- 2005-08-15
- Volume
- 132
- Issue
- 16
- Pages
- 3767-3776
- ISSN
- 0950-1991 (ISSN-L)
- 1477-9129
- OpenAlex
- W1982781304
- Cited by
- 344
- References
- 39
- Citations by year
- 2026: 7 · 2025: 6 · 2024: 10 · 2023: 17 · 2022: 15 · 2021: 17 · 2020: 14 · 2019: 12 · 2018: 12 · 2017: 14 · 2016: 14 · 2015: 13 · 2014: 24 · 2013: 29 · 2012: 23
- FWCI
- 9.95
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Development (publishedVersion)
- PubMed (publishedVersion)
- HighWire Press Open Archive (submittedVersion)
- Funders
- American Diabetes Association
- Vanderbilt University (CA68485)
- Johns Hopkins University
- Vanderbilt University Medical Center (CA68485)
- National Institutes of Health (CA68485, DK 20593)
- National Cancer Institute (R01CA098322, CA46413, CA-084239, CA68485, F32 CA 76698, U01CA084239, F32CA076698, CA-98322, R01CA046413, P30CA068485)
- National Institute of Diabetes and Digestive and Kidney Diseases (DK-58404, DK61215, DK 20593, DK-60694, R01DK061215, P30DK058404, R01DK060694)
- Topics
- Health Sciences › Medicine › Oncology › Pancreatic and Hepatic Oncology Research
- Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
- Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
- Keywords
- acinar-to-ductal metaplasia, EGFR signaling, pancreatic cancer precursors, lineage tracing, pancreatic development, epithelial metaplasia
- MeSH terms
- Animals, Cell Differentiation, Epithelium, Gene Expression Regulation, Humans, Intermediate Filament Proteins, Metaplasia, Mice, Transgenic, Nerve Tissue Proteins, Pancreas, Signal Transduction, Transforming Growth Factor alpha, Cell Lineage, Transgenes, Mice, Nestin, ErbB Receptors
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