Objective Here, we evaluate the contribution of AT-rich interaction domain-containing protein 1A (ARID1A), the most frequently mutated member of the SWItch/sucrose non-fermentable (SWI/SNF) complex, in pancreatic homeostasis and pancreatic ductal adenocarcinoma (PDAC) pathogenesis using mouse models.
Design Mice with a targeted deletion of Arid1a in the pancreas by itself and in the context of two common genetic alterations in PDAC, Kras and p53, were followed longitudinally. Pancreases were examined and analysed for proliferation, response to injury and tumourigenesis. Cancer cell lines derived from these models were analysed for clonogenic, migratory, invasive and transcriptomic changes.
Results Arid1a deletion in the pancreas results in progressive acinar-to-ductal metaplasia (ADM), loss of acinar mass, diminished acinar regeneration in response to injury and ductal cell expansion. Mutant Kras cooperates with homozygous deletion of Arid1a, leading to intraductal papillary mucinous neoplasm (IPMN). Arid1a loss in the context of mutant Kras and p53 leads to shorter tumour latency, with the resulting tumours being poorly differentiated. Cancer cell lines derived from Arid1a-mutant tumours are more mesenchymal, migratory, invasive and capable of anchorage-independent growth; gene expression analysis showed activation of epithelial-mesenchymal transition (EMT) and stem cell identity pathways that are partially dependent on Arid1a loss for dysregulation.
Conclusions ARID1A plays a key role in pancreatic acinar homeostasis and response to injury. Furthermore, ARID1A restrains oncogenic KRAS-driven formation of premalignant proliferative IPMN. Arid1a-deficient PDACs are poorly differentiated and have mesenchymal features conferring migratory/invasive and stem-like properties.
- pancreatic cancer
- cancer genetics
- pancreatic pathology
- epithelial differentiation
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WW and SCF contributed equally.
Contributors Conceived and designed the experiments: WW, SCF and AFH; acquisition of data: WW, SCF, BG, MRO and WBA); analysis and interpretation of data: WW, SCF, CLW-M, DA-V, ARH, JRM, JMA and AFH; drafted the manuscript: WW, SCF and AFH; statistical analysis: WW and SCF; revised the manuscript and agreed with the manuscript’s results and conclusions: all the authors; study supervision: AFH.
Funding AFH is supported by the John and Ethel Heselden Professorship, Pancreatic Cancer Association of Western New York, Michael Contestable Golf Tournament and NCI R01 CA172302. WW and BG are supported by internal funding through the Wilmot Cancer Research Fellowship Program.
Competing interests None declared.
Patient consent Not required.
Provenance and peer review Not commissioned; externally peer reviewed.
Data sharing statement The authors are willing to share the data related to any of the work reported.
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