Maintenance of acinar cell organization is critical to preventing Kras-induced acinar-ductal metaplasia
Open accessAbstract
Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers owing to a number of characteristics including difficulty in establishing early diagnosis and the absence of effective therapeutic regimens. A large number of genetic alterations have been ascribed to PDAC with mutations in the KRAS2 proto-oncogene thought to be an early event in the progression of disease. Recent lineage-tracing studies have shown that acinar cells expressing mutant Kras(G12D) are induced to transdifferentiate, generating duct-like cells through a process known as acinar-ductal metaplasia (ADM). ADM lesions then convert to precancerous pancreatic intraepithelial neoplasia (PanIN) that progresses to PDAC over time. Thus, understanding the earliest events involved in ADM/PanIN formation would provide much needed information on the molecular pathways that are instrumental in initiating this disease. As studying the transition of acinar cells to metaplastic ductal cells in vivo is complicated by analysis of the entire organ, an in vitro three dimensional (3D) culture system was used to model ADM outside the animal. Kras(G12D)-expressing acinar cells rapidly underwent ADM in 3D culture, forming ductal cysts that silenced acinar genes and activated duct genes, characteristics associated with in vivo ADM/PanIN lesions. Analysis of downstream KRAS signaling events established a critical importance for the Raf/MEK/ERK pathway in ADM induction. In addition, forced expression of the acinar-restricted transcription factor Mist1, which is critical to acinar cell organization, significantly attenuated Kras(G12D)-induced ADM/PanIN formation. These results suggest that maintaining MIST1 activity in Kras(G12D)-expressing acinar cells can partially mitigate the transformation activity of oncogenic KRAS. Future therapeutics that target both the MAPK pathway and Mist1 transcriptional networks may show promising efficacy in combating this deadly disease.
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Stabilized expression of PTF1A and MIST1 inhibits PanIN formation in the context of mutant KRAS expression.
“stabilized expression of PTF1A and MIST1 inhibit PanIN formation in the context of mutant KRAS expression122,123.”
From Pancreatic cancer: Advances and challenges (2023) · cites this paper as [123]
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- Authors
- Shi, G., DiRenzo, D., Qu, C., Barney, D., Miley, D., & Konieczny, S. F.
- Affiliations
- Purdue University West Lafayette (US)
- Corresponding author
- Konieczny, S F
- Venue
- Oncogene
- Published
- 2012-06-04
- Volume
- 32
- Issue
- 15
- Pages
- 1950-1958
- ISSN
- 0950-9232 (ISSN-L)
- 1476-5594
- PMC
- PMC3435479
- OpenAlex
- W2048669411
- Cited by
- 162
- References
- 47
- Citations by year
- 2026: 7 · 2025: 4 · 2024: 12 · 2023: 14 · 2022: 13 · 2021: 14 · 2020: 12 · 2019: 3 · 2018: 15 · 2017: 13 · 2016: 15 · 2015: 14 · 2014: 15 · 2013: 8 · 2012: 2
- FWCI
- 6.33
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Oncogene (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Purdue University
- National Institutes of Health
- National Cancer Institute (R01CA124586, CA124586)
- National Institute of Diabetes and Digestive and Kidney Diseases (DK55489, R01DK055489)
- Topics
- Health Sciences › Medicine › Oncology › Pancreatic and Hepatic Oncology Research
- Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Keywords
- acinar-to-ductal metaplasia, pancreatic ductal adenocarcinoma, KRAS G12D, Mist1, Raf/MEK/ERK pathway, MAPK signaling, pancreatic intraepithelial neoplasia, 3D organoid culture, pancreatic cancer initiation
- MeSH terms
- Animals, Carcinoma in Situ, Cell Line, Cell Transformation, Neoplastic, Metaplasia, Mice, Transgenic, Pancreatic Ducts, Pancreatic Neoplasms, Precancerous Conditions, Signal Transduction, Proto-Oncogene Proteins p21(ras), Carcinoma, Pancreatic Ductal, Extracellular Signal-Regulated MAP Kinases, raf Kinases, Mice, Basic Helix-Loop-Helix Proteins, Acinar Cells
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