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Updated: Feb 7, 2026
A Simple and Rapid Method for Simultaneous Isolation of Primary Islets and Primary Pancreatic Acinar Cells from Mice
Published on: January 9, 2026
The BRG1/SOX9 axis is critical for acinar cell-derived pancreatic tumorigenesis
Motoyuki Tsuda1, Akihisa Fukuda1, Nilotpal Roy2
1Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan.
Abstract:
Chromatin remodeler Brahma related gene 1 (BRG1) is silenced in approximately 10% of human pancreatic ductal adenocarcinomas (PDAs). We previously showed that BRG1 inhibits the formation of intraductal pancreatic mucinous neoplasm (IPMN) and that IPMN-derived PDA originated from ductal cells. However, the role of BRG1 in pancreatic intraepithelial neoplasia-derived (PanIN-derived) PDA that originated from acinar cells remains elusive. Here, we found that exclusive elimination of Brg1 in acinar cells of Ptf1a-CreER; KrasG12D; Brg1fl/fl mice impaired the formation of acinar-to-ductal metaplasia (ADM) and PanIN independently of p53 mutation, while PDA formation was inhibited in the presence of p53 mutation. BRG1 bound to regions of the Sox9 promoter to regulate its expression and was critical for recruitment of upstream regulators, including PDX1, to the Sox9 promoter and enhancer in acinar cells. SOX9 expression was downregulated in BRG1-depleted ADMs/PanINs. Notably, Sox9 overexpression canceled this PanIN-attenuated phenotype in KBC mice. Furthermore, Brg1 deletion in established PanIN by using a dual recombinase system resulted in regression of the lesions in mice. Finally, BRG1 expression correlated with SOX9 expression in human PDAs. In summary, BRG1 is critical for PanIN initiation and progression through positive regulation of SOX9. Thus, the BRG1/SOX9 axis is a potential target for PanIN-derived PDA.
Insights
The chromatin remodeler BRG1 (Brahma related gene 1) is crucial for initiating and progressing pancreatic intraepithelial neoplasia (PanIN) by regulating SOX9 expression. Targeting the BRG1/SOX9 pathway may offer new treatments for PanIN-derived pancreatic ductal adenocarcinoma.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Brahma related gene 1 (BRG1) is a chromatin remodeler frequently silenced in pancreatic ductal adenocarcinomas (PDAs).
- Previous studies linked BRG1 to the inhibition of intraductal pancreatic mucinous neoplasm (IPMN) and IPMN-derived PDA originating from ductal cells.
- The role of BRG1 in pancreatic intraepithelial neoplasia (PanIN)-derived PDA, originating from acinar cells, remained unclear.
Purpose of the Study:
- To investigate the function of BRG1 in PanIN initiation and progression originating from acinar cells.
- To elucidate the molecular mechanisms by which BRG1 influences PanIN development.
- To assess the therapeutic potential of targeting the BRG1/SOX9 axis in PanIN-derived PDA.
Main Methods:
- Utilized genetically engineered mouse models (Ptf1a-CreER; KrasG12D; Brg1fl/fl) with conditional Brg1 deletion in acinar cells.
- Investigated the impact of Brg1 deletion on acinar-to-ductal metaplasia (ADM) and PanIN formation, with and without p53 mutation.
- Employed a dual recombinase system to delete Brg1 in established PanIN lesions.
- Analyzed BRG1 binding to the Sox9 promoter and its effect on SOX9 expression and recruitment of regulatory factors like PDX1.
- Correlated BRG1 and SOX9 expression in human PDA samples.
Main Results:
- Exclusive Brg1 elimination in acinar cells impaired ADM and PanIN formation independently of p53 status.
- PDA formation was inhibited by Brg1 deletion only in the presence of p53 mutation.
- BRG1 directly regulates SOX9 expression by binding to its promoter and recruiting PDX1.
- SOX9 downregulation was observed in BRG1-deficient ADMs/PanINs, and Sox9 overexpression rescued the PanIN-attenuated phenotype.
- Brg1 deletion in established PanIN lesions led to lesion regression in mice.
- BRG1 expression positively correlated with SOX9 expression in human PDAs.
Conclusions:
- BRG1 is essential for the initiation and progression of PanIN lesions derived from acinar cells.
- BRG1 promotes PanIN development through the positive regulation of SOX9 expression.
- The BRG1/SOX9 signaling axis represents a promising therapeutic target for PanIN-derived PDA.
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