ARID1A Maintains Differentiation of Pancreatic Ductal Cells and Inhibits Development of Pancreatic Ductal Adenocarcinoma in Mice
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Background & aims The ARID1A gene encodes a protein that is part of the large adenosine triphosphate (ATP)-dependent chromatin remodeling complex SWI/SNF and is frequently mutated in human pancreatic ductal adenocarcinomas (PDACs). We investigated the functions of ARID1A during formation of PDACs in mice.Methods We performed studies with Ptf1a-Cre;Kras G12D mice, which express activated Kras in the pancreas and develop pancreatic intraepithelial neoplasias (PanINs), as well as those with disruption of Aird1a (Ptf1a-Cre;Kras G12D;Arid1a f/f mice) or disruption of Brg1 (encodes a catalytic ATPase of the SWI/SNF complex) (Ptf1a-Cre;Kras G12D; Brg1 f/f mice). Pancreatic ductal cells (PDCs) were isolated from Arid1a f/f mice and from Arid1a f/f;SOX9OE mice, which overexpress human SOX9 upon infection with an adenovirus-expressing Cre recombinase. Pancreatic tissues were collected from all mice and analyzed by histology and immunohistochemistry; cells were isolated and grown in 2-dimensional and 3-dimensional cultures. We performed microarray analyses to compare gene expression patterns in intraductal papillary mucinous neoplasms (IPMNs) from the different strains of mice. We obtained 58 samples of IPMNs and 44 samples of PDACs from patients who underwent pancreatectomy in Japan and analyzed them by immunohistochemistry.Results Ptf1a-Cre;Kras G12D mice developed PanINs, whereas Ptf1a-Cre;Kras G12D;Arid1a f/f mice developed IPMNs and PDACs; IPMNs originated from PDCs. ARID1A-deficient IPMNs did not express SOX9. ARID1A-deficient PDCs had reduced expression of SOX9 and dedifferentiated in culture. Overexpression of SOX9 in these cells allowed them to differentiate and prevented dilation of ducts. Among mice with pancreatic expression of activated Kras, those with disruption of Arid1a developed fewer PDACs from IPMNs than mice with disruption of Brg1. ARID1A-deficient IPMNs had reduced activity of the mTOR pathway. Human IPMN and PDAC specimens had reduced levels of ARID1A, SOX9, and phosphorylated S6 (a marker of mTOR pathway activation). Levels of ARID1A correlated with levels of SOX9 and phosphorylated S6.Conclusions ARID1A regulates expression of SOX9, activation of the mTOR pathway, and differentiation of PDCs. ARID1A inhibits formation of PDACs from IPMNs in mice with pancreatic expression of activated KRAS and is down-regulated in IPMN and PDAC tissues from patients.
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KRASQ61 mutant tumors have a decreased GTP hydrolysis rate with high RAF-dependent MEK phosphorylation and do not respond to SOS1 inhibition.
“On the other hand, KRASQ61 mutant tumors had a decreased GTP hydrolysis rate with high RAF-dependent MEK phosphorylation, and they did not response to SOS1 inhibition29,44.”
From Impact of KRAS mutations and co-mutations on clinical outcomes in pancreatic ductal adenocarcinoma (2024) · cites this paper as [44]
In mouse models, disrupted ARID1A promoted carcinogenesis from KRAS-mutated premalignant intraductal papillary mucinous neoplasms (IPMN) to PDAC.
“In mouse models, disrupted ARID1A promoted the carcinogenesis from KRAS-mutated premalignant intraductal papillary mucinous neoplasms (IPMN) to PDAC44.”
From Impact of KRAS mutations and co-mutations on clinical outcomes in pancreatic ductal adenocarcinoma (2024) · cites this paper as [44]
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- Authors
- Kimura, Y., Fukuda, A., Ogawa, S., Maruno, T., Takada, Y., Tsuda, M., Hiramatsu, Y., Araki, O., Nagao, M., Yoshikawa, T., Ikuta, K., Yoshioka, T., Wang, Z., Akiyama, H., Wright, C. V., Takaori, K., Uemoto, S., Chiba, T., & Seno, H.
- Affiliations
- Kyoto University (JP)
- University of Michigan (US)
- Gifu University (JP)
- Vanderbilt University (US)
- Corresponding author
- Fukuda, Akihisa
- ORCID
- Venue
- Gastroenterology
- Publisher
- Elsevier BV
- Published
- 2018-07
- Volume
- 155
- Issue
- 1
- Pages
- 194-209.e2
- ISSN
- 0016-5085 (ISSN-L)
- OpenAlex
- W2794844550
- Cited by
- 90
- References
- 59
- Citations by year
- 2026: 7 · 2025: 12 · 2024: 10 · 2023: 8 · 2022: 9 · 2021: 17 · 2020: 8 · 2019: 13 · 2018: 6
- FWCI
- 4.16
- Type
- journal article
- Language
- en
- Open access
- green
- hdl.handle.net
- Locations
- Gastroenterology (publishedVersion)
- PubMed (publishedVersion)
- Kyoto University Research Information Repository (Kyoto University) (submittedVersion)
- Funders
- Japan Society for the Promotion of Science (16K09394)
- National Heart, Lung, and Blood Institute (R01HL109054)
- Topics
- Health Sciences › Medicine › Oncology › Pancreatic and Hepatic Oncology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chromatin Remodeling and Cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
- Keywords
- ARID1A, pancreatic ductal adenocarcinoma, pancreatic ductal cells, SWI/SNF chromatin remodeling, SMARCA4, SOX9, pancreatic intraepithelial neoplasia, intraductal papillary mucinous neoplasm, KRAS G12D, cell differentiation, tumor suppression, adenoviral gene transfer
- MeSH terms
- Animals, Cell Differentiation, DNA-Binding Proteins, Nuclear Proteins, Pancreatic Ducts, Pancreatic Neoplasms, Transcription Factors, Proto-Oncogene Proteins p21(ras), Cell Culture Techniques, Carcinoma, Pancreatic Ductal, Mice, SOX9 Transcription Factor, Carcinogenesis, Adenocarcinoma in Situ
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