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Notch mediates TGFα-induced changes in epithelial differentiation during pancreatic tumorigenesis
Open accessAbstract
Notch signaling regulates cell fate decisions in a wide variety of adult and embryonic tissues. Here we show that Notch pathway components and Notch target genes are upregulated in invasive pancreatic cancer, as well as in pancreatic cancer precursors from both mouse and human. In mouse pancreas, ectopic Notch activation results in accumulation of nestin-positive precursor cells and expansion of metaplastic ductal epithelium, previously identified as a precursor lesion for pancreatic cancer. Notch is also activated as a direct consequence of EGF receptor activation in exocrine pancreas and is required for TGF alpha-induced changes in epithelial differentiation. These findings suggest that Notch mediates the tumor-initiating effects of TG alpha by expanding a population of undifferentiated precursor cells.
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“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 [111]
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Self-citation
Metadata
- Authors
- Miyamoto, Y., Maitra, A., Ghosh, B., Zechner, U., Argani, P., Iacobuzio-Donahue, C. A., Sriuranpong, V., Iso, T., Meszoely, I. M., Wolfe, M. S., Hruban, R. H., Ball, D. W., Schmid, R. M., & Leach, S. D.
- Affiliations
- Johns Hopkins University (US)
- Universität Ulm (DE)
- Gunma University (JP)
- Fox Chase Cancer Center (US)
- Harvard University (US)
- Corresponding author
- Leach, Steven D.
- ORCID
- Venue
- Cancer Cell
- Publisher
- Elsevier BV
- Published
- 2003-06
- Volume
- 3
- Issue
- 6
- Pages
- 565-576
- ISSN
- 1535-6108 (ISSN-L)
- OpenAlex
- W2148054025
- Cited by
- 643
- References
- 69
- Citations by year
- 2026: 3 · 2025: 5 · 2024: 7 · 2023: 11 · 2022: 17 · 2021: 19 · 2020: 15 · 2019: 15 · 2018: 33 · 2017: 27 · 2016: 26 · 2015: 27 · 2014: 34 · 2013: 36 · 2012: 37
- FWCI
- 15.11
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cancer Cell (publishedVersion)
- PubMed (publishedVersion)
- mediaTUM – the media and publications repository of the Technical University Munich (Technical University Munich) (submittedVersion)
- Funders
- National Institutes of Health
- National Cancer Institute (CA 70244, F32 CA 76698, R01CA070244, F32CA076698, P50CA062924, CA 62924)
- National Institute of Diabetes and Digestive and Kidney Diseases (DK56211, R01DK056211, DK61215, R01DK061215)
- National Institute of Neurological Disorders and Stroke (R01NS041355, NS41355)
- Topics
- Health Sciences › Medicine › Oncology › Pancreatic and Hepatic Oncology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Pancreatic function and diabetes
- Keywords
- Notch signaling, transforming growth factor-alpha, pancreatic cancer, pancreatic carcinogenesis, epithelial differentiation, pancreatic cancer precursors, EGF receptor activation, tumor initiation, exocrine pancreas
- MeSH terms
- Animals, Cell Differentiation, Cells, Cultured, Epithelial Cells, Humans, Intermediate Filament Proteins, Membrane Proteins, Mice, Transgenic, Neoplasm Invasiveness, Nerve Tissue Proteins, Pancreatic Neoplasms, Signal Transduction, Biomarkers, Up-Regulation, Transforming Growth Factor alpha, Disease Progression, Oligonucleotide Array Sequence Analysis, Gene Expression Profiling, Carcinoma, Ductal, Mice, Receptors, Notch, Nestin, ErbB Receptors
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